nature reviews bioengineering https://doi.org/10.

1038/s44222-023-00040-w

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Delivery technologies for

women’s health applications
Kelsey L. Swingle    1, Adele S. Ricciardi    2, William H. Peranteau3 & Michael J. Mitchell    1,4,5,6,7,8 
Abstract Sections

The treatment of women’s health-related conditions, including Introduction

reproductive tract and pregnancy disorders, faces distinct challenges Delivery technologies in
and microenvironments, such as the vaginal mucosa and the placenta, non-pregnant women

which may be overcome by nanotechnology- and biomaterials-based Delivery technologies in

pregnant women
drug delivery technologies. Here, we discuss the design and optimization
of therapeutic nanoparticle and biomaterial systems to deliver drugs Outlook

for the treatment of conditions in non-pregnant and pregnant women,

including vaginal infections, reproductive tract disorders, pregnancy
conditions and fetal congenital disorders. We highlight how drug
delivery systems can be engineered for specific administration routes
such as vaginal, in utero and intraperitoneal administration, to penetrate
biological barriers such as the vaginal mucosa, and to provide sustained
and efficient drug delivery at the site of interest. Although these
delivery systems have mainly been explored in preclinical settings thus
far, implementing women-specific design considerations in delivery
technologies will allow their optimization and clinical translation for the
treatment of women’s health conditions.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. 2Department of Surgery, University
1

of Pennsylvania Health System, Philadelphia, PA, USA. 3The Center for Fetal Research, Division of General, Thoracic,
and Fetal Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 4Abramsom Cancer Center,
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5Institute for Immunology, Perelman
School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 6Cardiovascular Institute, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7Institute for Regenerative Medicine, Perelman School
of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Penn Institute for RNA Innovation, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA.  e-mail: mjmitch@seas.upenn.edu

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Key points high mucin content contribute to a complex microenvironment that

must be considered when designing delivery technologies for vaginal
administration14,15. Similarly, preferential delivery to the reproduc-
•• Several barriers, challenges and microenvironments that are unique tive tract is essential for local or systemically administered platforms
to the female body must be considered in the design of delivery designed to treat endometriosis or gynaecological cancers. Moreover,
technologies for women’s health applications. thorough, long-term studies evaluating impacts on fertility are equally
important. In pregnancy, the placenta is a complex barrier that can be
•• Biomaterial systems can be engineered to deliver drugs for the exploited for selective delivery to the mother or fetus with carefully
treatment of vaginal infections, gynaecological cancers, endometriosis, designed delivery systems16. Although the consideration of mother and
pregnancy disorders and congenital disorders in utero. fetus as a single entity during pregnancy is a complex social construct,
the administration of drugs and biomaterials during pregnancy is sug-
•• In addition to efficacy, the safety and toxicity of delivery systems are gested to have long-term developmental effects on the fetus that are
key design considerations for the treatment of women’s health-related still not completely understood17 (Box 1).
conditions. In this Review, we discuss engineered biomaterials and delivery
technologies for reproductive health challenges in non-pregnant
•• Appropriate and accessible preclinical models are essential for the (Fig. 1a) and pregnant (Fig. 1b) women, with an emphasis on design con-
clinical translation of delivery technologies for women’s health, but siderations that exploit the biological barriers and microenvironments
the physiological and pathophysiological differences amongst species unique to women’s health. We highlight polymer, lipid and inorganic
must be considered. nanoparticles, as well as natural and synthetic biomaterial platforms,
such as scaffolds and hydrogels that can deliver small-molecule drugs,
•• The engineering of delivery systems for women’s health can build on such as chemotherapeutics and antibiotics, nucleic acids, such as small
delivery technologies that have shown clinical success in other disease interfering RNA (siRNA) and messenger RNA (mRNA), and biologics,
applications. such as proteins and antibodies, for the treatment of vaginal infections,
reproductive tract disorders, pregnancy-related conditions, and in
utero therapies for fetal congenital disorders. Understanding women-
Introduction specific biomaterial design considerations is key to the optimization
Women’s health concerns the study and treatment of conditions that and clinical translation of delivery technologies for the treatment of
disproportionately affect women, including reproductive tract and women’s reproductive health conditions.
pregnancy disorders. Although many delivery technologies have
been explored and some clinically approved for various applications, Delivery technologies in non-pregnant women
including cancer, immunotherapy, vaccines and gene therapy, their Vaginal infections
application in women’s health remains limited1–3. This can be partially The vagina is a flexible, muscular canal that extends from the outside
explained by the disparity between the preclinical funding and disease of the female genital area to the cervix (Fig. 2a). The vaginal lumen is
burden for women-specific disorders, compared with men-specific lined with two distinct layers of mucus: the luminal mucus layer, which
disorders4; for example, for almost 75% of disorders that affect primar- is rapidly cleared, and the adherent mucus layer, which is slowly cleared.
ily one gender, US federal funding favours men4. In addition, wom- Cervicovaginal mucus is composed primarily of water and contains only
en’s health research must consider the complex social sensitivities 5–8% of solid material, predominantly mucin glycoproteins, proteo-
in reproductive health and the mother and fetus as a single entity5. glycans and lipids14. The primary purpose of cervicovaginal mucus is
As a result, only 3.7% of all clinical trials from 2007 to 2020 focused to trap and clear pathogens, preventing them from entering the body
on female gynaecology, demonstrating not only the preclinical chal- and infecting the underlying epithelium14.
lenges of women’s health research, but also the limited clinical trans- Vaginal infections include bacterial infections such as chlamydia
lation of therapies6 (Box 1). This Review uses the terms ‘women’ and and gonorrhoea, fungal infections such as vulvovaginal candidiasis (the
‘woman’ throughout; we recognize that not all those who experience common yeast infection Candida albicans), and sexually transmitted
menstrual cycles, pregnancy and endometriosis identify as women. viral infections such as human immunodeficiency virus (HIV), human
Engineered biomaterial and drug delivery systems have many papilloma virus (HPV) and herpes virus. Clinically approved treatments
advantages over traditional drug formulations, including improved for these infections include oral antibiotics, antivirals and antifungals,
cargo stability, increased transport across cellular barriers, controlled as well as vaginal suppositories, creams, tablets and rings that act as
release, and local administration and retention1,2,7–9. In 1991, Norplant drug depots (Fig. 2b). Oral treatments for vaginal infections have several
was the first FDA-approved drug delivery system for women’s health10. limitations, including the high doses required to achieve therapeutically
Norplant is a subdermal contraceptive implant consisting of six silicone relevant levels of antibiotic or antifungal in the vaginal tissue.
capsules encapsulating the synthetic hormone levonorgestrel. This Alternatively, local administration of suppositories and creams
technology was followed by the approval of the transdermal contra- exploits several advantages of vaginal delivery, including avoiding first-
ceptive patch Ortho Evra and the contraceptive vaginal ring NuvaRing pass clearance and dilution effects, which are commonly observed with
in 200111,12. systemically administered drugs18. Upon vaginal administration, the first
Drug delivery platforms must consider the barriers, microenvi- uterine pass effect may allow preferential drug accumulation in the uterus
ronments and challenges specific to women’s reproductive health; for and vagina through counter-current drug exchange between the blood
example, the vaginal mucosa can be exploited for potent local delivery in vaginal veins and the uterine artery19. The effect was first observed in a
to the reproductive tract through the ‘first uterine pass effect’ (direct human ex vivo uterine perfusion model, in which high concentrations of
vagina-to-uterus transport)13. In addition, the vaginal microbiota and vaginally administered, radioactively labelled progesterone accumulate

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in the uterine endometrium and myometrium20,21. In addition, higher

plasma levels of vaginally administered progesterone are observed in the
uterine artery, as compared with the radial artery, in post-menopausal
Box 1
women22. However, differences in the anatomy and physiology of the
vagina amongst species raise concerns about whether the first uterine Translational considerations
pass effect applies to all animal models23,24 (Box 2).
Vaginal delivery systems can also take advantage of the rich blood Sex-specific differences
supply and high vaginal surface area, caused by the abundance of folds, Sex-specific differences for disorders that disproportionately or
which aid in drug absorption18. However, current clinically used vaginal solely affect women need to be better understood to improve our
suppositories and creams have limited efficacy owing to self-cleaning biological and mechanistic understanding of these disorders185–187,
of the vagina that results in low residence time25. Therefore, engineered and to identify therapeutic targets that might address the underlying
biomaterial and nanoparticle drug delivery systems can improve the disease pathology rather than the associated symptoms.
treatment of vaginal infections.
Diagnostics
Bacterial and fungal infections. Some of the most common vaginal Diagnostic platforms need to be developed that enable the early
bacterial infections include Neisseria gonorrhoeae (gonorrhoea) and detection of women’s health conditions; for example, the Pap smear
Chlamydia trachomatis (chlamydia)25–27. The World Health Organiza- for cervical cancer and the Mirvie RNA platform for pregnancy
tion (WHO) estimates that over 100 million cases of gonorrhoea and complications188–190.
over 80 million cases of chlamydia occur per year28. Fortunately, these
infections are curable with antibiotics26. Local antibiotic administra- Funding
tion in the vagina is preferred over oral administration, because it Funding designated for women’s health research will allow the devel-
enables higher local drug concentrations and minimizes effects on opment and accessibility of robust preclinical models for women’s
the gastrointestinal tract microbiome26. However, drugs are quickly health. Many delivery technologies are only evaluated in vitro or in
cleared from the vagina because of self-cleaning and leakage caused small rodent models; however, larger animal models will be essential
by gravity and walking (Table 1). for the clinical translation of therapeutics and delivery technologies.
Bioadhesive delivery systems adhere to the vaginal mucosa, in par-
ticular to the mucin glycoproteins in the cervicovaginal mucus layers29, Clinical trials
and thus improve drug residence time. The anionic glycosylated regions Clinical trial guidelines need to be adapted to include pregnant
of mucin mediate bioadhesion through covalent bonding and ionic inter- women in clinical trials, including those for pregnancy-specific
actions with positively charged macromolecules such as chitosan29,30 complications191. Data on human fetal safety is lacking for ~90% of
(Fig. 2c). Therefore, nanoparticle delivery systems made of natural prescription medications192,193, and therefore pregnant women with
polymeric materials, such as chitosan, have been explored for treating chronic illnesses are often untreated during pregnancy owing to
vaginal bacterial infections25,27. For example, in vitro antibacterial activity the risk of negatively affecting the fetus194. For example, pregnant
has been demonstrated against several strains of gonorrhoea, including women were excluded from the COVID-19 vaccine trials, requiring
those resistant to multiple antibiotics, with unloaded chitosan micropar- clinicians to create their own recommendations for pregnant
ticles, as chitosan itself has antibacterial activity27. Chitosan nanoparti- women with little scientific evidence to support them.
cles can also be loaded into polymeric nanofibre formulations made from
polyvinylpyrrolidone, or gel formulations made from cellulose deriva- Racial disparities
tives, such as hydroxypropyl methylcellulose (HPMC), to generate com- Racial disparities need to be addressed that are responsible for
bination therapies with dual mucoadhesive effects31 (Fig. 2c). In an ex vivo higher rates of preterm birth and maternal mortality in black women
model using sheep vaginal tissue, polyvinylpyrrolidone nanofibres and compared with white women, considering the institutions, social
HPMC gels loaded with drug-containing chitosan nanoparticles increase constructs and communities in which pregnant women are living195,196.
mucoadhesion compared with free drug formulations31. Alternatively,
liposomes encapsulating anti-inflammatory small molecule drugs can
be loaded into mucoadhesive chitosan hydrogels, and have been shown vagina33,35. Drug efficacy can be improved by using biomaterial-based
to inhibit in vitro nitric oxide production in lipopolysaccharide-induced delivery systems; for example, film and gel polymeric delivery systems
macrophages32. Moreover, antibiotic-loaded silicone emulsions have formulated with chitosan show better inhibition of C. albicans, com-
demonstrated mucoadhesive properties with in situ residence in the pared with free drug formulations, in vitro33,34. Similarly, a polymeric gel
vaginal tissue of rats for up to 24 h following vaginal administration, and emulsion of miconazole improves antifungal activity against C. albicans
liquid crystal lipid emulsions have improved the in vitro antibacterial infection in rats, compared with a clinically approved vaginal supposi-
activity of ciprofloxacin against Escherichia coli, compared with free tory formulation of the same drug36. Biomaterials allow control and
antibiotics, in infected reproductive tract epithelial cells18,26. tuning of the release of antifungal agents; for example, by altering the
Candida albicans is responsible for vulvovaginal candidiasis, concentration of sodium alginate in polymer gel formulations, in vitro
also known as the vaginal yeast infection. In their lifetime, 70–75% of antifungal drug release in simulated vaginal fluid can be modulated37.
women experience vulvovaginal candidiasis, most often treated with Polymeric nanoparticle formulations can greatly improve the sustain-
oral antifungal agents33–35. Oral treatments, however, are not ideal for ability of drug release, compared with free drugs37,38. Polymeric gel
vaginal infections, and antifungal agents, such as voriconazole and and liposome delivery systems can also increase ex vivo or in vivo anti-
ketoconazole, have poor aqueous solubility, necessitating their encap- fungal drug retention in vaginal tissues35,39; for example, vaginally
sulation in delivery devices for local drug release and retention in the administered liposomes preferentially accumulate in the reproductive

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a Non-pregnant women

Endometriosis Vaginal infections Gynaecological cancers

Ovarian cancer Cervical cancer

Delivery technologies Delivery technologies Delivery technologies

Drug-conjugate Metal-oxide Silver Emulsion Nanofibre Natural or synthetic Antibody/peptide Microparticle

NP NP polymeric NP decorated NP capsule

Therapeutics Therapeutics Therapeutics

Antibiotic Antiviral siRNA Chemotherapeutic Cytokine Anti-

Photothermal siRNA miRNA inflammatory
agent drug

b Pregnant women

Spina bifida Delivery technologies Pre-term birth Delivery technologies

Microparticle ECM
capsule scaffold Hydrogel Liposome Dendrimer

Therapeutics Therapeutics

Anti- Hormone
Growth factor Cell inflammatory
drug

In utero gene therapy Pre-eclampsia and fetal growth restriction

Delivery technologies Delivery technologies

Pre-eclampsia Normal
pregnancy

Synthetic Antibody/peptide
Polymeric NP Lipid NP Drug-conjugate polymeric NP decorated NP

Therapeutics Therapeutics

mRNA pDNA Gene editing siRNA pDNA Growth factor

cargo

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Fig. 1 | Delivery technologies for women’s health applications. a, Reproductive and fetal congenital disorders. Various delivery technologies and cargoes can be
health challenges in non-pregnant women include endometriosis, gynaecological applied for the treatment of these conditions. ECM, extracellular matrix; miRNA,
cancers and vaginal infections, including bacterial, fungal and sexually microRNA; mRNA, messenger RNA; NP, nanoparticle; pDNA, plasmid DNA; siRNA,
transmitted infections. b, Reproductive health challenges in pregnant women small interfering RNA.
include pregnancy disorders, such as pre-eclampsia and fetal growth restriction,

tract of rats with similar cytokine levels to those of the control group, vaginal tissue of combination therapies that contain PEGylated nano-
and show higher retention in porcine vaginal tissue ex vivo, compared particles and mucoadhesive polymeric fibres58. Alternatively, hyper-
with the free drug39. Importantly, using the rabbit vaginal irritation branched polyglycerols can improve the bioadhesion of polymeric
assay, the only FDA-approved animal model for testing vaginal irrita- particles encapsulating an antiretroviral small molecule59, resulting in
tion, the liposomes do not cause any histological changes in the vaginal nearly 5 times as much retention of the nanoparticles, compared with
tissue39. Of note, safety and toxicity of vaginally administered thera- the non-adhesive control nanoparticles, in the murine reproductive
peutics have to be evaluated, because biomaterial-induced irritation tract 24 hours after vaginal administration59. Therefore, biomaterials
or inflammation can make the vagina more susceptible to additional can address several delivery challenges for vaginal infection, including
infections39. Together, delivery devices can improve the solubility, mucus adhesion and penetration, and vaginal retention and stability
antifungal activity, sustained release and vaginal retention of antifungal in the acidic vaginal microenvironment.
agents, compared with free drug formulations.
Reproductive tract disorders
Sexually transmitted viral infections. Unlike for bacterial and fungal The female reproductive tract consists of the vulva, vagina, cervix,
infections, for which antibiotics and small molecules have mainly uterus, fallopian tubes and ovaries. Endometriosis and gynaecologi-
been explored, various cargos have been investigated for the prophy- cal cancers are two major disorders affecting the female reproductive
lactic treatment of viral infections, including antivirals40–44, nucleic tract. Endometriosis involves the formation of benign lesions out-
acids45–48, biologics49 and small molecules50,51. Delivering nucleic acids, side the reproductive tract, sharing many physiological traits with
such as siRNA, is particularly challenging for vaginal infections owing malignant gynaecological cancers. For example, both endometriotic
to the dependence on charge-based electrostatic interactions for and cancerous lesions are invasive and can induce inflammation and
many delivery systems and the acidic pH (3.5–4.0) of the vagina45,52. angiogenesis60, which can cause high rates of relapse.
In vivo siRNA-mediated knockdown of enhanced green fluorescent
protein (EGFP) has been achieved in the murine vaginal mucosa by Endometriosis. Endometriosis is a hormone-dependent gynaecologi-
using poly(lactic-co-glycolic acid) (PLGA) nanoparticles47; here, sper- cal disorder, defined as the presence of endometrial tissue outside the
midine was used as a low-molecular-weight cationic agent to complex uterus. Endometriosis affects about 10–15% of women at the reproduc-
the negatively charged siRNA and improve cargo loading in the PLGA tive age61,62, and numerous endometriosis-related complications can
nanoparticle by >40-fold47,48. However, nucleic acid delivery systems occur, including chronic pelvic pain and infertility; however, there are
typically contain a cationic or ionizable component to enable endo- currently no curative treatments for endometriosis62. Clinical treat-
somal escape of the nucleic acid at acidic pH2,53. To avoid premature ment typically includes hormonal therapies to suppress oestrogen
cargo release in the acidic environment of the vagina, a pH-responsive synthesis, small-molecule drugs to manage pain, and surgical inter-
film can protect solid lipid nanoparticles encapsulating siRNA45. In vention by laparoscopy to remove endometriotic lesions60. However,
simulated vaginal fluid, the nanoparticle-loaded film demonstrates hormonal therapy can have long-term and systemic adverse side
little to no release of solid lipid nanoparticles at acidic pH, but shows effects, and endometriotic lesions recur in 40–50% of women who
increased cargo release with increasing pH45. This system could be have undergone surgery62.
applied for anti-HIV prophylaxis, ensuring drug release only on expo- Polymeric implantable drug delivery systems can mediate sus-
sure to seminal fluid during heterosexual intercourse, whereby vaginal tained drug release from the peritoneum into the uterus and to endo-
pH increases toward neutral. metriotic lesions, with sustained in vitro release of small-molecule
Drug penetration through cervicovaginal mucus layers into the drugs for up to 30 days62,63. In addition to locally administered systems,
underlying epithelium can be improved by functionalization of poly- selective and active targeting approaches have been explored for the
meric nanoparticles with hydrophilic polymers, such as poly(ethylene treatment of endometriotic lesions. Selective drug delivery, for exam-
glycol) (PEG)54–56 (Fig. 2c). Such mucus-penetrating particles show ple by distinct cargo selection and design, to ectopic endometriotic
higher vaginal retention and coverage in mice, compared with non- lesions rather than healthy endometrial tissue is essential to minimize
functionalized nanoparticles56. Here, oestradiol was used to induce negative effects on female fertility64 (Table 1). A polymer/nucleic acid
the oestrus phase in mice before vaginal administration of nanopar- conjugate comprising miR-200c, a microRNA (miRNA) significantly
ticles to better mimic the cervicovaginal mucus of humans56 (Box 2). downregulated in ectopic endometriotic lesions compared with nor-
These mucus-penetrating particles also better protect mice against a mal endometrial tissue, reduces ectopic endometrial cyst volume in an
vaginal herpes simplex virus 2 challenge, compared with the soluble autotransplantation rat model of endometriosis65. miR-200c interacts
drug56. In addition, unlike mucus-penetrating nanoparticles, vaginal with the untranslated regions of mRNA to trigger translational repres-
administration of non-functionalized nanoparticles causes neutrophil sion or mRNA degradation, thereby suppressing the proliferation and
infiltration into the vaginal lumen, indicating better biocompatibility migration of endometrial cells, and reducing the volume of the cyst.
of PEG-functionalized particles56. PEG-functionalization also improves Similarly, micelle systems and polymeric or peptide conjugates can
the ex vivo penetration in sheep vaginal epithelium of liposomes that deliver small-molecule drugs or siRNA against targets that are upregu-
deliver drugs against HPV infection57, and the in vivo retention in murine lated in endometriotic lesions66–68; for example, overexpression of

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a Fundus Fig. 2 | Design of delivery technologies for the

of uterus vaginal microenvironment. a, The vagina extends
Fallopian tube Cervicovaginal mucus layers
from the cervix to the external genitalia, and its lumen
Vaginal lumen is lined with two layers of cervicovaginal mucus: the
Luminal luminal mucus layer, which is rapidly cleared, and
mucus layer the adherent mucus layer, which is more slowly cleared.
Ovary (rapidly cleared) b, Clinically used therapies for vaginal infections
Uterus Adherent
Uterine cavity include oral medications, vaginal suppositories,
Cervix mucus layer
(slowly cleared)
creams, tablets and prophylactic vaginal rings for
Cervical canal
sexually transmitted infection. Delivery technologies
Epithelium such as nanoparticles (NPs), gels, nanofibres and films
Vagina
can improve the delivery and efficacy of clinically used
therapeutics. c, Technologies for vaginal drug delivery
should consider the vaginal mucus layers, as these may
b limit the penetration of the delivery platform into the
Clinical therapies for vaginal infections Preclinical delivery technologies
underlying epithelium, which is often the target for
for vaginal infections
vaginally administered therapeutics. Functionalizing
nanoparticles with hydrophilic polymers, such as
Oral antibiotics, Suppositories Tablets NPs Nanofibres poly(ethylene glycol) (PEG), creates a water sheath
antivirals or
around the nanoparticles that can aid in mucus
antifungals
NP-loaded gel penetration. Delivery technologies can be designed
to be mucoadhesive, for example by formulation or
Rings Creams Mucus-penetrating NPs Films functionalization with mucoadhesive molecules to
improve adhesion to mucin. Nanoparticles can also be
c encapsulated in gel formulations to improve retention
Penetration Mucoadhesion and retention in the vaginal lumen.
– – –
Mucin
– – ––
PEG – –– – –
– – – – –
– –
– – – – – –
– – – –
NP – – + + +
+ +
+ + Mucoadhesive
+ + molecule
+ + +
Water sheath

Mucus-penetrating
NPs NPs

NPs or drugs in
gel formulations

low-density lipoprotein (LDL) in endometriotic lesions can be targeted Inorganic nanoparticle platforms can also be used as imaging
by lipid nanoparticles that resemble the native structure of LDL69. contrast and photothermal therapy agents for the identification and
These particles can deliver small-molecule drugs specifically to endo- treatment of endometriotic lesions71,72; for example, hyaluronic-acid-
metrial tissues69. Alternatively, active targeting enables preferential modified iron oxide nanoparticles aided in the visualization of endo-
localization of delivery technologies in endometriotic tissue; for exam- metriotic tissue using magnetic resonance imaging, two hours after
ple, silver nanoparticles functionalized with peptides that recognize intravenous nanoparticle administration, in an autotransplantation rat
extracellular matrix (ECM) receptors upregulated in endometriotic model of endometriosis71. Nanoparticles can further improve surgical
lesions enable the targeted delivery of antimitotic drugs60. Similarly, resection of lesions; for example, PEG-poly(caprolactone) (PCL) poly-
peptide–siRNA conjugates can target receptors that are critical to meric nanoparticles encapsulating silicon naphthalocyanine allow real-
the development of endometriosis, thereby inhibiting the migration time near-infrared fluorescence imaging and photothermal therapy of
and invasion of endometrial cells outside the uterus60,64. Iron oxide endometriotic lesions72, demonstrating demarcation, and, on exposure
nanoparticles coated with peptides that bind to vascular endothelial to near-infrared light, complete eradication of endometriotic lesions
growth factor receptor 2 selectively accumulate in endometriotic transplanted from rhesus macaques into immunodeficient mice. The
lesions, generating sufficient ablation temperatures on exposure to effectiveness and clinical relevance of such nanoparticle platforms
an alternating magnetic field to completely eradicate endometriotic depend on the specificity of markers to the ectopic endometriotic
lesions in a mouse xenograft model of endometriosis70 (Box 2). lesions of interest.

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Gynaecological cancers. Gynaecological cancers include ovarian, off-target toxicity that may impact fertility. For example, nanoparti-
cervical, uterine, vaginal and vulval cancer. Bioengineering research cles can be functionalized with antibody or peptide motifs for selective
has thus far mainly focused on developing therapeutics for ovarian and localization to a specific tissue or cell type9. For the treatment of ovarian
cervical cancer. With the highest mortality rate of all gynaecological and cervical cancer, delivery systems can be functionalized with epi-
cancers, ovarian cancer also has a high rate of recurrence and a five- dermal growth factor receptor (EGFR) antibodies, human epidermal
year survival rate of less than 50%73–75, partly owing to the asympto- growth factor receptor 2 (HER2) antibodies, arginine–glycine–aspartic
matic nature of stage I and stage II ovarian cancer, resulting in 75% of acid (RGD) peptides, luteinizing-hormone-releasing hormone recep-
diagnoses occurring at late stages76. Cervical cancer is more common tor (LHRH) peptides, cell-penetrating peptides and single-stranded
in developing regions, where there is limited access to prophylactic DNA aptamers73–75,78,79,81–83; for example, PCL nanoparticles modified
vaccines against human papilloma virus (HPV) infection, which is highly with LHRH peptides increase drug localization within the tumour,
associated with the development of cervical cancer77–79. However, owing compared with the free drug and non-targeted nanoparticles, in a
to the availability of the Papanicolaou (Pap) test, early detection of mouse xenograft model for ovarian cancer74. Alternatively, through
cervical cancer is more feasible and accessible than for ovarian cancer80 layer-by-layer assembly84–87, the core or surface of nanoparticles can
(Box 1). Chemotherapeutic regimens for ovarian cancer often involve be modified with hyaluronic acid, which binds to CD44 receptors on
intravenous co-administration of a free platinum-based drug, such as ovarian cancer cells84,86.
cisplatin, and a taxane chemotherapeutic, such as paclitaxel; these To address the recurrence of ovarian and cervical cancer, delivery
chemotherapeutic regimens typically supplement surgical resection systems can be designed to achieve sustained release of encapsulated
of the ovary or tumour75. Similarly, clinical treatment of cervical can- drugs (Table 1); for example, chemotherapeutics can be encapsu-
cer involves surgery or radiotherapy for early-stage cancer, with the lated in injectable or implantable hydrogel formulations to reduce
addition of chemotherapy for late-stage disease78. side effects and tumour size with a single local hydrogel injection,
Targeted delivery can improve the localization and efficacy of compared with multiple injections of free drug88–90. In a mouse xen-
drugs against reproductive cancerous tissues and minimize their ograft model for ovarian cancer, tumour burden can be reduced

Box 2

Limitations of preclinical in vivo models

Vaginal infections models are limited in their ability to mimic tumour initiation201.
Both humans and rodents have cyclic menstrual or oestrus cycles; Alternatively, genetically engineered mouse models can be used
however, differences in the gross anatomy of the reproductive to study tumour initiation, but these are difficult to generate, partly
tract and vaginal tissue may limit the applicability of rodents owing to the limited understanding of the biology of ovarian cancer
for the investigation of women’s health-related conditions. For and the infertility that results from transgenic ovarian cancer
example, the vaginal epithelium in rodents is keratinized and its models201.
thickness varies with the oestrus phase, which could affect the
ability to extrapolate results evaluating the permeability of delivery Pregnancy-related conditions
technologies to humans23,197. In addition, animal models, such as Humans, rodents, guinea pigs, rabbits and non-human primates
rodents, which are often used to evaluate the efficacy of delivery have haemochorial placentas; by contrast, pigs and sheep
technologies for sexually transmitted infections, do not accurately (with epitheliochorial placentas) and dogs (with endotheliochorial
represent the human vaginal microbiota198, undervaluing the role placentas) are not clinically relevant models for studying
of the vaginal microbiota in host–pathogen interactions198. pregnancy-related conditions119,120. In addition, many commonly
used rodent models have haemotrichorial placentas, as opposed
Endometriosis to humans, who have haemomonochorial placentas120.
Rodent models are typically of short duration (that is, days to
weeks) and therefore can only mimic the early stages of peritoneal Spina bifida
endometriosis199, making them less clinically relevant for studying Valproic- or retinoic-acid-induced spina bifida is an easily
late-stage endometriosis199. Unlike in humans, endometriosis does not accessible model in rodents, mimicking the scenario in which
occur spontaneously in rodents, rabbits and hamsters, but does occur women take anticonvulsants during pregnancy and are thus at
spontaneously in some non-human primate species200. However, the increased risk of having a fetus with spina bifida202,203. However,
occurrence of spontaneous endometriosis is lower in non-human these models do not mimic complex aspects of the disease.
primates than in humans, and diagnosing disease onset is limited Alternatively, surgical introduction of a spinal defect in fetal sheep
owing to the lack of non-invasive methods for early detection200. more closely reflects the morphological and functional effects of
spinal cord damage in humans204,205, but such large animal models
Ovarian cancer are costly, resource-intensive and have lower throughput than
Rodent xenograft models have been established for ovarian cancer, smaller rodent models.
mimicking various aspects of the human disease; however, these

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Table 1 | Preclinical delivery technologies and their design considerations for women’s health applications

Design considerations Application Delivery technology Therapeutic cargo Refs.

Vaginal infections

Retention: self-cleaning action of the Bacterial infections Chitosan–alginate microspheres Antibiotic 25

vagina and leakage owing to walking and

gravity limit in situ drug residence Chitosan nanoparticles NA 27

Penetration: delivery technologies must Nanoparticle-loaded gel Small molecule 31,32

adhere to and penetrate the vaginal

mucosa to deliver their cargo to the Polymeric and lipid emulsions Antibiotic 18,26

underlying epithelium
Fungal infections Liposomes Small molecule 39

Stability: vaginal pH ranging from 3.8

to 4.5 can affect the stability of delivery Polymer emulsion Antifungal 33,35–37

technologies
Polymeric films Antifungal 34

Chitosan-modified polymeric Antifungal 38

nanoparticles

Sexually transmitted Polymeric nanoparticles Antiretroviral, siRNA, fluorescent 44,47,48,

viral infections dye 54–56,59,170

Chitosan-polymeric particles Inhibitor peptide 49

Nanoparticle-loaded polymeric films Antiretroviral 40,42

Nanoparticle-loaded polymeric Antiretroviral or siRNA 45,58

nanofibres

Polymeric nanocrystals Antiretroviral 50

Silk fibroin Antiviral 41

Liposomes Cytokine 57

Lipid emulsion siRNA or small molecule 46,171

Silver nanoparticles Small molecule 51

Polymeric nanoparticle-loaded gel Antiviral 43

Reproductive tract disorders

Specificity: delivery to healthy, non- Endometriosis Peptide-functionalized silver Small molecule 60

endometriotic or non-cancerous tissues nanoparticles

can lead to infertility
Polymer or peptide conjugate siRNA 64,67,68
Recurrence: sustained release of one
or more encapsulated cargos may limit Polymeric nanoparticles miRNA, antibody, NIR contrast 61,65,72

recurrence and relapse agent

Administration route: systemic
Polymeric nanofibres or films Small molecule 62,63
(intravenous) versus local (intraperitoneal
and intravaginal) delivery routes may Polymer-modified iron oxide NA 71

enable delivery to different organs nanoparticles

Gynaecological Polymeric nanoparticles Chemotherapeutic, photosensitizer, 74,75,77,83–85,

cancers small molecule, or siRNA 87,93,95,96,172

Polymeric nanocrystal loaded hydrogel Chemotherapeutic 80,89,173

Iron oxide nanoparticles Unloaded or small molecule 174,175

Polymeric hydrogels Chemotherapeutic 88,90,176

Solid lipid nanoparticles Chemotherapeutic or 76,78,81

photosensitizer

Selenium nanoparticles siRNA 73,79

Cell-membrane-coated mesoporous Chemotherapeutic and 177

nanoparticle photosensitizer

Gold nanoparticle siRNA 82

Peptide conjugate Anticancer drug 178

Silica nanoparticles Nucleic acid 97

Polymer–lipid nanoparticles Chemotherapeutic 86,179

Alginate microparticles Cytokine-expressing epithelial cells 91

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Table 1 (continued) | Preclinical delivery technologies and their design considerations for women’s health applications

Design considerations Application Delivery technology Therapeutic cargo Refs.

Pregnancy-related conditions
Target: delivery systems may be designed Understanding drug Polymer conjugate Small molecule 107,110

to deliver cargos preferentially to the and nanoparticle

mother, fetus or placenta biodistribution in Gold nanoparticles NA 111–113,117,180

Stability: premature drug release from pregnancy Liposomes Fluorescent marker 130

delivery systems can result in off-target

drug delivery, which may be toxic for the Iron oxide nanoparticles NA 181

fetus Polymeric nanoparticles Fluorescent marker 114–116,182

Immunogenicity: pregnancy disorders are

often associated with complex immune Polymer–lipid nanoparticles Small molecule 108,183

and inflammatory responses that can be Preterm birth Silk protein hydrogel NA 121,123,125
exacerbated by foreign biomaterials and
result in fetotoxic effects Polymeric nanoparticle- loaded gel Small molecule 19,126

Polymeric nanoparticles Small molecule 124

Liposomes Contraction-blocking drug 122,129

Pre-eclampsia Peptide conjugate miRNA inhibitor 141

and fetal growth

restriction (FGR) Lipid conjugate siRNA 184

Liposomes Nitric oxide donor or growth factor 132,142,143

Polymeric nanoparticles pDNA or siRNA 133,138,140

Polymer–lipid nanoparticles siRNA 131,144

In utero therapies for congenital disorders

Administration route: injection routes, Gene therapies Lipid conjugate pDNA 155

such as vitelline vein and intra-amniotic

administration, are only available before Polymeric nanoparticles PNAs/DNA or fluorescent marker 145,147

birth and may improve organ specificity Lipid nanoparticles mRNA 146,150

Stability: microenvironments, such as the

amniotic fluid, are dynamic in gestation Liposomes pDNA 154

and can pose distinct protein content and Spina bifida Polymer hydrogel Unloaded, small molecule, fetal 156,161–163

pH challenges for delivery systems fibroblasts, or growth factor

Immunogenicity: the naive fetal immune
system limits the foreign biomaterial Polymer scaffold Fetal chondrocytes, stem cells, or 164–166

immune response compared with stromal cells

postnatal treatments Alginate particles Growth factor or fluorescent marker 148,157

Acellular tissue patch NA 158,159

Polymeric patch NA 160

mRNA, messenger RNA; miRNA, microRNA; NA, not applicable; NIR, near-infrared; pDNA, plasmid DNA; PNA, peptide nucleic acid; siRNA, small interfering RNA.

with a single intratumoural injection of a platinum-based, thermo- mucoadhesion, mucus penetration and retention for cervical cancer
sensitive polymeric gel system loaded with paclitaxel, compared applications80,93,94.
with multiple systemic injections of free chemotherapeutic88. Local In addition, new cargos are being explored to avoid drug resistance
injection or implantation, such as intraperitoneal administration, for recurrent gynaecological cancers. For example, siRNA, photo­
can further minimize the dilution effect of therapeutic cargo as well sensitizers for photothermal therapy, microRNA inhibitors, and
as off-target side effects that may result from systemic administra- small-molecule drugs, such as poly(ADP-ribose) polymerase inhibitors,
tion91; for example, an alginate microparticle capsule encapsulating curcumin and histone deacetylase inhibitors77,86,95–98, can be delivered in
cells that stably express interleukin-2 (IL-2) can be intraperitoneally combination with chemotherapeutics; however, new animal models for
injected for ovarian cancer cytokine immunotherapy91,92, achiev- recurrent ovarian and cervical cancer would be needed to investigate
ing therapeutically relevant levels of IL-2 in the peritoneal fluid for their efficacy and to evaluate repeated dosing and drug resistance.
15 days post-capsule administration and near complete eradica-
tion of tumours in a murine xenograft model of advanced ovarian Delivery technologies in pregnant women
cancer. Alternatively, drugs can be intravaginally delivered for Pregnancy-related conditions
cervical cancer treatment, which requires distinct design consid- Conditions that develop during pregnancy are complex and difficult to
erations for the delivery system, including drug retention in the treat owing to the synergistic effects on the mother, fetus and placenta.
vagina and penetration through the mucus to the underlying vagi- The placenta is an organ and biological barrier unique to pregnancy
nal epithelium; in particular, nanoparticle surface functionaliza- that develops in the uterus in early gestation and mediates exchange of
tion and drug encapsulation in a hydrogel formulation can improve nutrients, oxygen and waste between maternal and fetal circulation16

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a
Maternal side
Maternal
blood
Uterine Cross-section of chorionic villus
space
wall
Maternal
vein Decidua
Basal lamina
Maternal
Spiral artery Fetal blood space
arteries
Fetal endothelial cell
Chorionic
Fetal Cytotrophoblast
villus
Umbilical artery
Maternal blood space
cord Fetal vein
Syncytiotrophoblast
Fetal side

b Pre-eclampsia c Placental structure across species

Organ level Healthy pregnancy Pre-eclampsia Haemomonochorial Haemodichorial Haemotrichorial

• Human • Rabbit • Mouse
• Non-human primates • Rat
• Guinea pig • Hamster
Spiral
Uterine
arteries
myometrium
Fetal
capillary
Extravillous
trophoblasts Cytotrophoblast
Decidua
Syncytiotrophoblast

Placenta
High blood flow Low blood flow

Cell level Single layer of Complete layer of Two cytotrophoblast layers

syncytiotrophoblast cytotrophoblast cells in addition surrounding syncytiotrophoblast
Flt-1 to syncytiotrophoblast layer layer
VEGF
PIGF sFlt-1
↑ sFlt-1
↓ Soluble VEGF and PIGF

Fig. 3 | Physiology of the human placenta in healthy and pre-eclamptic of extravillous trophoblasts into the uterus and decidua results in lower blood
pregnancies. a, The placenta is an organ of both maternal and fetal origin that flow in the placenta, which can lead to maternal hypertension and lower fetal
develops during early gestation to supply nutrients and oxygen to the fetus by birth weights. On a cellular level, dysregulation in angiogenic factors, such as
mediating exchange between maternal and fetal circulation. The decidua is vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF),
the first layer of the placenta located on the maternal side, which forms upon also plays a role in placental insufficiency disorders. Upregulation of soluble
implantation of the blastocyst in the uterine wall through a process called fms-like tyrosine kinase 1 (sFlt-1), the soluble version of the VEGF and PlGF
decidualization. Remodelling of the uterine tissue allows maternal spiral receptor, is observed in the serum of pre-eclamptic women, which decreases
arteries to extend into the placenta and to supply blood to the chorionic villi. the bioavailability of VEGF and PlGF to mediate vasodilation in the placenta. c,
These villi are the site of oxygen and nutrient transport to the fetus, and they Rodents, hamsters, rabbits, guinea pigs, non-human primates and humans have
separate the maternal and fetal blood spaces by means of layers of villous haemochorial placentas, which are defined by the presence of trophoblast-lined
trophoblasts (the syncytiotrophoblast and cytotrophoblasts) as well as fetal chorionic villi that are directly exposed to maternal blood. However, the nature
endothelial cells. b, In healthy pregnancies, extravillous trophoblasts invade of trophoblast cell layer(s) differs amongst species, which can affect the utility of
the decidua and uterine myometrium, remodelling the spiral arteries to create these animal models as representations of human conditions during pregnancy.
a high-blood-flow environment to meet the oxygen and nutrient demands of Panel a adapted from ref. 103, Springer Nature Limited.
the fetus. In pre-eclampsia and fetal growth restriction, inefficient invasion

(Fig. 3a). On the maternal side of the placenta is the decidua, which is artery remodelling by invading the decidua and uterine wall to create a
a thick mucosal membrane that contains placental immune cells and high-blood-flow environment99,102. Insufficient spiral artery remodel-
regulates cell invasion into the uterus99,100. In a process called deciduali- ling and placentation can result in placental insufficiency disorders,
zation, the decidua forms following implantation of the blastocyst into such as pre-eclampsia99 (Fig. 3b).
the uterine wall and induces remodelling of uterine tissue. The maternal The placenta can be exploited as a biological barrier for selective
spiral arteries extend from the uterine wall through the decidua and therapeutic delivery to the mother, fetus or placenta during pregnancy
supply blood to chorionic villi — the site of blood exchange between (Table 1). However, to treat maternal, fetal or placental disorders with
maternal and fetal circulation101. In healthy pregnancies, extravillous drug delivery systems, their behaviour and placental transport during
trophoblasts, one of the main cell types in the placenta, mediate spiral pregnancy must be well characterized.

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Understanding drug and nanoparticle biodistribution in pregnancy. preclinical model to study delivery technologies for pregnancy appli-
Besides mediating nutrient and oxygen transport between the mother cations. Humans have haemochorial placentas, defined by the pres-
and fetus, the placenta also minimizes the transport of toxins from ence of trophoblast-lined chorionic villi that are directly exposed to
maternal to fetal circulation101. This is achieved through a complex maternal blood119 (Fig. 3a), limiting the use of large species, such as
layer of cells, including the syncytiotrophoblast, cytotrophoblasts and pigs and sheep (with epitheliochorial placentas), and dogs (with endo-
fetal endothelial cells that separate maternal and fetal blood spaces in theliochorial placentas), as appropriate preclinical models for preg-
the chorionic villi103 (Fig. 3a). As gestation proceeds, cytotrophoblasts nancy applications119,120. By contrast, rodents, guinea pigs, rabbits
progressively fuse into the syncytiotrophoblast, which is a continuous, and non-human primates have haemochorial placentas and are thus
epithelial syncytial structure that serves as the endocrine portion of common preclinical models for studying placental development,
the placenta by producing vascular endothelial growth factor (VEGF) delivery and transport119 (Fig. 3c). In particular, humans, non-human
and placental growth factor (PlGF) to mediate vasodilation and angio- primates and guinea pigs have haemomonochorial placentas with a
genesis104–106. Although this layer of trophoblasts and fetal endothelial single layer of syncytiotrophoblast in the chorionic villi. Conversely,
cells functions as the barrier between maternal and fetal blood spaces, rabbits have haemodichorial placentas with one complete layer of
many small-molecule drugs can transport across the placenta, and cytotrophoblast cells in addition to the syncytiotrophoblast layer,
some can induce fetal malformations16,107,108. For this reason, pregnant whereas rats, mice and hamsters have haemotrichorial placentas with
women are often advised to restrict their intake of small molecules, three distinct trophoblast layers119. These differences in placentation
including antiepileptic drugs, depression and anti-anxiety medications, must be considered when evaluating therapeutics for pregnancy, parti­
antibiotics and chemotherapeutics, owing to potential harmful effects cularly when studying placental transport; the presence of additional
on fetal development. However, discontinuing these medications can cell layers in rodent placentas is likely to affect the extrapolation of
also have detrimental effects on pre-existing maternal disorders when results from these models to humans (Box 2).
unmanaged during pregnancy109. To address this challenge, drugs can
be conjugated to polymers to increase their size and limit placental Preterm birth. Preterm birth is defined as the premature delivery of the
transport107,110; for example, a PEG–drug conjugate shows less placental fetus, before 37 weeks of gestation19,121,122. Globally, an estimated 15 million
uptake than the free drug in an ex vivo human placental explant model107, babies are born prematurely every year, and preterm birth is the leading
demonstrating the potential of delivery systems to reduce placental cause of neonatal mortality and morbidity19,122. Like many conditions
transport and increase drug localization in maternal circulation. that develop during pregnancy, preterm birth is a multifactorial disor-
Reducing placental transport is not the only consideration for der, with potential causes including cervical insufficiency, intrauterine
minimizing fetotoxic effects. Indirect effects can also occur, including inflammation and premature onset of uterine contractions123,124.
maternal-mediated fetotoxicity and placental-mediated fetotoxicity, Cervical insufficiency resulting in a shortened cervix has been asso-
where delivery of foreign materials to maternal organs or the placenta ciated with an increased risk of preterm birth and is often treated with
can induce oxidative stress and consequently inflammation, which can cervical cerclage, whereby the cervix is supported and closed with a
impair fetal development17 (Table 1). Therefore, in addition to evaluating stitch placed vaginally or abdominally121,123. However, cerclage therapy
direct fetotoxicity (that is, the presence of the drug or delivery technol- has the risk of cervical tissue damage or laceration, in particular if the
ogy in fetal tissues), these indirect fetotoxic effects must be evaluated cerclage is present during labour121,125. As cervical cerclage does not
to ensure the safety of the platform before clinical translation. address the underlying pathogenesis of cervical insufficiency, that is, the
The pharmacokinetics and biodistribution of drugs during preg- impaired mechanical properties of the fibrous connective tissue of
nancy can be modulated by encapsulating drugs in nanoparticles. Here, the cervix, preterm birth can still occur following cerclage therapy121,125.
the physicochemical properties of the nanoparticles, such as size, charge To address tissue softening in cervical insufficiency, silk-fibroin-based
and surface modification, have a substantial impact on their biodistribu- hydrogels can be injected directly into the cervix to increase cervical tis-
tion during pregnancy111–116; for example, 15-nm gold nanoparticles have sue volume121,123,125. Such hydrogels promote the viability and proliferation
higher accumulation in placental tissue than 150-nm gold nanoshells113, of cervical fibroblasts in vitro, and lead to a substantial increase in the
and increasing the molecular weight of elastin-like polypeptide drug cross-sectional area of the cervix in pregnant rabbits121,125. In addition to
conjugates from 25 kDa to 86 kDa can also improve accumulation in increasing tissue volume, the silk hydrogel may also improve resistance
the placenta110. Regarding charge, cationic polymeric nanoparticles against stresses that act to dilate the cervix and induce preterm birth125.
have higher accumulation and penetration in placental cells than do Progesterone is the only FDA-approved therapeutic agent for
more anionic delivery systems114,115, and surface modifications, such as treating preterm birth126, and can either be used alone or to supplement
PEGylation, carboxylation or addition of targeting moieties, can improve cerclage therapy. Since its approval in 1956, intramuscular injection of syn-
cellular uptake in or transport across the placenta111,112,116. thetic progestin had been administered to millions of pregnant women
In addition, gestational age has a substantial impact on the ability in the United States, but progestin was removed from the market in 1973
to deliver drugs to the placenta, transport across the placenta to the owing to a lack of evidence in preventing preterm birth127. In 2011, the FDA
fetus, and consequently fetal survival113,114,117, which may be explained by approved Makena for the treatment of preterm birth after a randomized,
the physiological changes in placental development that occur during double-blind clinical trial with 463 women demonstrated a reduction in
gestation. For example, in humans, the surface area of chorionic villi the risk of recurrent preterm birth with synthetic progestin128. However, in
and the volume of the intervillous space increase throughout gesta- 2020, the FDA proposed to withdraw approval for Makena after a second
tion to increase the efficiency of exchange between maternal and fetal clinical trial with 1,708 women demonstrated no significant differences
circulation118. For similar reasons, the thickness of the syncytiotropho- in neonatal outcomes compared with the placebo group126,128. In 2022, an
blast and fetal endothelium decreases during the last two trimesters. increased risk of cancer was reported in the offspring of women treated
Therefore, differences in placental structure and develop­ment between with intramuscular synthetic progestogen, further raising concerns
species are a major consideration for selecting the most appropriate over the safety of the therapeutic127. Therefore, delivery technologies

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are required that enable selective progestogen delivery to the uterus and fetus fails to achieve their full growth potential in utero, which can lead
cervix with minimal negative effects on fetal health. to impaired respiratory development and higher chance of infection, as
As an alternative to systemically administered Makena, Crinone is well as long-term risks of cardiovascular disease and type 2 diabetes132,133.
a commercially available, vaginal progesterone gel for the treatment of Preclinical therapeutics that address placental dysfunction, under-
reproductive disorders, which has been used off-label as a prophylactic lying these disorders, are often administered systemically, aiming to miti-
drug for preterm birth126. As a vaginal gel, Crinone can take advantage gate impaired vascularization by targeting placental trophoblasts and
of the first uterine pass effect, resulting in selective drug accumulation endothelial cells134,135. Intravenous administration is often preferred for
in the uterus126. To further improve drug accumulation in the uterus and therapeutic delivery to the placenta owing to the cardiovascular changes
prevent preterm birth, polymeric nanoparticles can be loaded in gel that occur during pregnancy, including a 45% increase in total cardiac
systems to deliver progesterone or histone deacetylase inhibitors19,126. output by 24 weeks of gestation, compared with non-pregnant individu-
These platforms show more effective prevention of preterm birth in als136. Of the total cardiac output, 20–25% represents blood flow to the
progesterone antagonist or lipopolysaccharide-induced murine mod- uterus and placenta, demonstrating the potential for high localization
els of preterm birth, compared with Crinone19,126. In addition, the expres- of intravenously administered delivery systems in the placenta137.
sion of inflammatory cytokines, such as interleukin (IL)-6, IL-1β, and Nanoparticles made of polyamidoamine (PAMAM) and encapsulat-
cyclooxygenase (COX)-2, increases in the uterine myometrium in mice ing soluble fms-like tyrosine kinase 1 (sFlt-1) siRNA can exploit passive
treated with the Crinone vaginal gel, compared with the nanoparticle- placental targeting during pregnancy for treating pre-eclampsia138, by
in-gel formulation, indicating potentially better safety profiles19. There- knocking down sFlt-1, which is an antiangiogenic factor upregulated
fore, biomaterial delivery systems may prolong drug release, increase during pre-eclampsia and secreted by the placenta138. sFlt-1 is the soluble
retention and improve stability, compared with free drugs. receptor for VEGF and PlGF and acts by binding to the receptor binding
Systemically administered delivery systems encapsulating small- domains of these growth factors, preventing their ability to interact
molecule drugs are also being explored for the treatment of other with trophoblast or endothelial cell surface receptors and resulting
conditions associated with preterm birth, including intrauterine in vascular  dysfunction104 (Fig. 3b). The PAMAM nanoparticles can
inflammation and premature contractions. For example, dendrimer reduce maternal blood pressure, proteinuria and serum sFlt-1 levels
nanoparticles encapsulating N-acetyl-L-cysteine, an antioxidant small in an induced tumour necrosis factor alpha (TNF-α) rat model of pre-
molecule with anti-inflammatory properties, can reduce the rate of pre- eclampsia138, without gross morphological changes in the histological
term birth and T-cell immune infiltration to the placenta in a lipopoly- analysis of the major organs. Of note, as pre-eclampsia is believed to
saccharide-induced murine model of preterm birth124. Alternatively, the occur spontaneously only in humans and non-human primates, preclini-
tocolytic agent indomethacin can be delivered in targeted liposomes cal models generated with the administration of exogenous agents can
to inhibit uterine contractions122,129. Indomethacin is a small molecule often only model portions of the disorder (that is, exacerbated maternal
and member of the non-steroidal anti-inflammatory drug family, and immune response)139 (Box 2). Alternatively, gene therapies for angio-
can freely cross the placenta; however, indomethacin has also been genic factors, such as insulin-like growth factor (IGF), can be delivered
associated with negative fetal development side effects and adverse to treat pre-eclampsia and FGR133,140; for example, a diblock copolymer
effects on maternal cardiovascular health122,129. Encapsulating the drug delivery system encapsulating IGF plasmid DNA that possesses the addi-
in targeted liposomal nanoparticles, typically about 200 nm in size, can tional design feature of trophoblast-specific promoters133,140 achieves
minimize drug transport across the placenta and decrease systemic trophoblast-specific gene expression in immortalized trophoblast cell
drug dosing. The liposomes can be further functionalized with an lines, with the potential to reduce off-target effects compared with other
antibody against the oxytocin receptor, which is highly expressed in the systemically administered nanoparticle technologies.
uterus of pregnant women122,129, to improve nanoparticle localization To improve nanoparticle uptake in the placenta in the treatment of
in the mouse uterus, compared to non-targeted systems, and to reduce pre-eclampsia and FGR, delivery systems can be modified with placenta-
accumulation in the fetus, compared with the free drug control122,129. specific targeting moieties; for example, peptide-decorated nanopar-
To promote clinical translation of these liposomes, however, their ticles can deliver cargos such as miRNA inhibitors, nitric oxide donor,
stability in vivo needs to be improved to limit premature drug release epidermal growth factor and IGF132,141–143. In addition to new synthetic
before uterine localization and to prevent free drug transport across peptide sequences, peptides targeting chondroitin sulfate A, a protein
the placenta that may harm the fetus. present on the surface of placental trophoblasts, can be used to localize
nanoparticles in the placenta131,144; for example, chondroitin-sulfate-A-
Pre-eclampsia and fetal growth restriction. Pre-eclampsia and fetal targeted polymeric nanoparticles encapsulating sFlt-1 siRNA decrease
growth restriction (FGR) are multifactorial placental disorders that the circulating levels of sFlt-1 in a genetically engineered mouse model
affect 5–8% and 7–15% of all pregnancies worldwide, respectively130. Pre- of pregnancy-associated hypertension, compared with non-targeted
eclampsia is defined as the onset of hypertension and proteinuria after nanoparticles, and decrease the rate of maternal and neonatal mortal-
20 weeks of gestation, posing a risk of seizures, pulmonary embolism, ity144. These preclinical studies demonstrate that nanoparticles and
renal failure, liver dysfunction, and maternal and fetal death131. Clinical biomaterials can deliver a variety of therapeutics to treat placental
treatments for pre-eclampsia, such as antihypertensive drugs to manage disorders, such as pre-eclampsia and FGR, and may allow the design
blood pressure and anticonvulsants to prevent seizures131, only address of combination therapies by combining multiple delivery systems
the associated symptoms rather than placental dysfunction, which is
often the underlying cause. The only curative treatment option for pre- In utero therapies for congenital disorders
eclampsia is the induction of labour and early delivery of the placenta and Advances in prenatal diagnostics, such as genetic testing through detec-
fetus, which often resolves maternal hypertension within a few days132. tion of cell-free fetal DNA in maternal circulation and high-resolution
However, early induction of labour can cause fetal morbidity and mortal- ultrasound, have enabled the early diagnosis of genetic disorders and
ity, especially if FGR occurs concurrently with pre-eclampsia. In FGR, the birth defects in utero145,146, including haemoglobinopathies such as

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β-thalassaemia, congenital lung disorders such as cystic fibrosis and postnatal treatment options, in utero therapies have the advantage
diaphragmatic hernia, and spinal defects such as spina bifida145,147,148. that the tolerogenic fetal immune system and small fetal size allow
Prenatal diagnostics can identify these disorders early in gestation; treatment with foreign materials with minimal fetal immune response
however, in utero treatment options for haemoglobinopathies and and maximal dosing per fetal weight145,151. Thus far, viral platforms
congenital lung disorders remain elusive. In the prenatal treatment of have mainly been explored for in utero gene therapy owing to their
myelomeningocele, which is the most common form of spina bifida, the well-studied, efficient gene transduction151,152. However, viral plat-
Management of Myelomeningocele Study demonstrated the benefits forms can potentially lead to ectopic integration into offsite regions
of prenatal surgical intervention, compared with postnatal surgery149. of the genome and may be immunogenic for the mother147,153. Alter-
However, both open surgical repair and fetoscopic surgery may lead to natively, non-viral delivery technologies may enable in utero gene
maternal complications and increased occurrence of premature rup- therapy.
ture of membranes148,149. Therefore, biomaterials and delivery systems Only a few nanoparticle delivery technologies have been devel-
are being explored for in utero intervention. oped for in utero gene therapy thus far (Fig. 4a, Table 1). Nanoparti-
cles encapsulating therapeutics can be intravenously administered
Gene therapies. In utero gene therapy may enable protein replace- to the fetus by injection into the vitelline vein, which drains directly
ment and gene editing therapy to treat congenital disorders, such into the fetal liver, the site of hematopoeisis146,147. This administration
as β-thalassaemia or cystic fibrosis, before birth150. Compared with route simulates umbilical vein blood transfusions, which have been

a In utero gene therapy b Therapies for spina bifida and myelomeningocele

Vitelline vein injection Fetoscopic surgery

Thalassaemia, anaemia, lysosomal storage disorders

Placenta Vessel Endothelial cells

HSC

RBCs
Vitelline or
umbilical vein Hepatoblast
(fetal precursor
of the hepatocyte)
Nucleic-
acid-loaded
nanoparticles

Intra-amniotic injection
Cystic fibrosis, surfactant protein syndromes, alpha-1 antitrypsin deficiency

Fluid-filled
lumen

Epithelium Cells
Basement
membrane
Ciliated Basal Endothelium Polymeric and ECM scaffolds
cell cell Blood
Amniotic
sac

Nucleic- Alginate Natural and synthetic

acid-loaded microparticles polymer patches
nanoparticles

Fig. 4 | In utero therapies for congenital disorders. a, In utero gene therapy (HSCs). Alternatively, intra-amniotic injections take advantage of fetal breathing
allows treatment of congenital disorders before the onset of irreversible disease and swallowing of the amniotic fluid to deliver gene therapeutics to the fetal lungs
pathology through protein replacement therapy or gene editing therapeutics. and treat disorders such as cystic fibrosis and surfactant protein syndromes.
These nucleic acid cargos are encapsulated in nanoparticle delivery systems and b, Delivery technologies can also be applied to treat congenital structural
can be administered through the vitelline vein or by intra-amniotic injections abnormalities, including spina bifida, in utero. For example, cell-seeded polymeric
in utero. Vitelline vein injections are comparable to umbilical vein transfusions and extracellular matrix (ECM) scaffolds, natural and synthetic polymer patches, and
performed clinically and provide direct access to the fetal liver to treat congenital drug-loaded alginate microparticles can be used to protect and repair spinal
disorders, such thalassaemia and anaemia, by targeting hematopoietic stem cells defects associated with these congenital disorders. RBC, red blood cell.

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performed safely in humans since the 1980s147. Both polymeric and In the clinic, MMC is treated prenatally by open or fetoscopic surgi-
lipid nanoparticles (LNPs) can deliver nucleic acids to the fetal liver cal repair of the defect; however, these treatment strategies may cause
through intravenous administration; for example, peptide nucleic premature labour148,157 (Fig. 4b) and are only offered at a few fetal sur-
acids and donor DNAs can be delivered by intravenously injected PLGA gery centres worldwide148,149. Alternatively, less-invasive intra-amniotic
nanoparticles to correct a mutation in the β-globin gene in a mouse administration of therapeutics using a amniocentesis-related proce-
model of β-thalassaemia147. Importantly, both polymeric and lipid- dure can promote protection and healing of an MMC defect148,157; for
based delivery platforms have demonstrated minimal toxicity for the example, alginate microparticles loaded with basic fibroblast growth
dam, as assessed by cytokine analyses. In addition, they have no effects factor can be intra-amniotically administered to improve soft tissue
on fetal survival. Non-hepatic delivery to the fetal lung, intestines and coverage in a retinoic-acid-induced rat model of MMC157. However,
brain may also be achievable145–147. rigorous testing in large animal models will be required to demonstrate
Alternatively, intra-amniotic administration of gene therapeutics the safety of this platform.
mimics amniocentesis procedures, which are used clinically to sample Matrix and scaffold biomaterials have also been investigated to
amniotic fluid during gestation for genetic testing147 (Fig. 4a). This improve soft tissue coverage and repair during fetoscopic surgery.
route of administration provides the opportunity to target organs, For example, natural biomaterials, such as cryopreserved human
such as the fetal lung and intestine, that are challenging to reach post- umbilical cord and acellular dermal matrix patches, and synthetic
natally through systemic administration routes145,147,150. Intra-amniotic polymer patches have been evaluated in vivo to cover and repair
administration takes advantage of fetal breathing and swallowing of the open spina bifida defects158–160. In a surgically induced sheep model
amniotic fluid, but requires consideration of the stability and dilution of spina bifida, a human umbilical cord patch can better repair the
of delivery platforms in the large volume of amniotic fluid150,151. The defect than a biocellulose film158, and compared with an acellular
stability of LNPs in amniotic fluid can be assessed through ex utero dermal matrix patch in a retinoic-acid-induced rat model of spina
screening of different LNP formulations in a series of amniotic fluids, bifida, the human umbilical cord patch can reduce acute inflamma-
with the aim to achieve mRNA-mediated in utero protein replace- tion and improve cellular growth at the defect site159. In addition,
ment therapy150. mRNA LNP formulations that are stable ex utero in polymeric gel systems can be chemically functionalized to adhere
amniotic fluid mediate higher in utero protein expression compared in the amniotic fluid environment and protect an MMC defect161,162.
with unstable LNP formulations150. Thus, the material composition of Scaffold materials, such as gelatin, collagen, chitosan and ECM, can
nanoparticles should be optimized to prevent aggregation and deg- further encapsulate cells or therapeutics for additional regenera-
radation in the protein-rich environment of amniotic fluid. Moreover, tive effects156,163–166; for example, treatment of surgically induced
cell-level delivery of polymeric nanoparticles has been explored in fetal MMC defects in time-dated ewes with small-intestine-derived ECM
lungs, including fetal lung epithelial cells, which are the target popu- seeded with placental mesenchymal stromal cells improves neuron
lation for treating cystic fibrosis and surfactant protein syndromes cell density and motor function, compared with defects treated with
in utero145. Polymeric nanoparticles (250 nm) of polyamine-co-ester ECM scaffolds alone164. Similarly, hybrid gelatin–collagen scaffolds
(PACE) administered intravenously to gestational-age E15 fetal mice encapsulating basic fibroblast growth factor cause the formation
enabled accumulation in up to 50% and 44% of lung epithelial and of granulation tissue to preserve the spinal cord in a retinoic-acid-
endothelial cells, respectively145. induced rat model of MMC163. Toxicity to both mother and fetus will
Transplacental delivery of non-viral delivery platforms provides need to be assessed for these platforms.
an alternative to vitelline vein or intra-amniotic administration to reach
the fetus in utero154,155. For example, delivery technologies encapsulat- Outlook
ing nucleic acids can be systemically administered to the pregnant Clinically translatable therapeutics for women’s health applications
dam through tail vein injections; here, delivery to the fetus relies on may greatly benefit from delivery technologies that have already been
transport across the placenta. Plasmid DNA–lipid conjugates can explored and tested in other applications, such as cancer and vaccines.
cross the placenta and deliver the plasmid to fetal hearts in a trans- However, the behaviour of delivery systems during pregnancy and
genic mouse model, which can be quantified by knockout of EGFP155. their capacity to treat pregnancy-related conditions remain poorly
Similarly, transplacental delivery of antibody-targeted liposomes understood. Indeed, a consensus on the ideal therapeutic target or
encapsulating reporter plasmid DNA leads to luciferase expression in type of cargo has not yet been reached for the treatment of many
neonatal brains, 48 hours following tail vein administration to pregnant women’s health-related conditions (Table 1). Therefore, new combi-
dams154. Although encouraging, neither maternal and fetal toxicity nor nations of delivery systems and cargos should be explored to identify
long-term neonatal survival have been assessed here, which would be formulations that can treat women’s health-related disorders most
important in evaluating an active targeting platform that crosses the effectively.
blood–brain barrier. Importantly, the most suitable administration route has to be
identified for targeting a specific organ, including consideration
Spina bifida. Spina bifida is a hereditary congenital disorder that would of the microenvironment and its impact on the delivery technol-
be likely to benefit from in utero prenatal treatment to minimize the ogy. Intravaginal delivery allows delivery to the vaginal epithelium
onset of irreversible disease pathology. Open spina bifida, or mye- but requires platforms to penetrate the thick vaginal mucosa. In
lomeningocele (MMC), is defined as the presence of a protruding and utero delivery, including intra-amniotic administration, provides the
non-neurulated spinal cord through the back, caused by failed fusion opportunity to target the fetal skin or lungs before birth; however,
of the vertebrae148,156. In utero, chemical and mechanical interactions of the amniotic fluid has not yet been well explored and has distinct
the exposed spinal cord with the amniotic fluid and surrounding protein and pH conditions that may affect the stability and efficacy of
membrane lead to neural toxicity148. Therefore, prenatal intervention delivery systems. In addition, the pharmacokinetics, biodistribution,
strategies and therapies are being explored for MMC. placental transport, and maternal and fetal safety of delivery systems

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Review article

need to be established, which are affected by their size, charge and 11. Smallwood, G. H. et al. Efficacy and safety of a transdermal contraceptive system.
Obstet. Gynecol. 98, 799–805 (2001).
composition (Box 1). 12. Roumen, F. J. M. E., Apter, D., Mulders, T. M. T. & Dieben, T. O. M. Efficacy, tolerability and
Delivery technologies for anticancer therapy and cancer immuno- acceptability of a novel contraceptive vaginal ring releasing etonogestrel and ethinyl
therapy have been studied for decades, with the first liposomal drug oestradiol. Hum. Reprod. 16, 469–475 (2001).
13. De Ziegler, D., Bulletti, C., De Monstier, B. & Jääskeläinen, A.-S. The first uterine pass
delivery platform for the chemotherapeutic drug doxorubicin gaining effect. Ann. N. Y. Acad. Sci. 828, 291–299 (1997).
FDA approval in 19951,167. Lessons can be learned from the cancer drug 14. Adnane, M., Meade, K. G. & O’Farrelly, C. Cervico-vaginal mucus (CVM) — an accessible
delivery field to apply these technologies in women’s health applica- source of immunologically informative biomolecules. Vet. Res. Commun. 42, 255–263
(2018).
tions; for example, endometrial lesions and placental cells share many 15. Gajer, P. et al. Temporal dynamics of the human vaginal microbiota. Sci. Transl. Med. 4,
physiological features with cancer60,132. Tumour-homing peptides can 132ra52–132ra52 (2012).
also be applied to target extravillous trophoblasts in the placenta, 16. Figueroa-Espada, C. G., Hofbauer, S., Mitchell, M. J. & Riley, R. S. Exploiting the placenta
for nanoparticle-mediated drug delivery during pregnancy. Adv. Drug Deliv. Rev. 160,
which behave similarly to metastatic cancer cells by invading the wall 244–261 (2020).
of the uterus and remodelling the uterine spiral arteries during preg- 17. Dugershaw, B. B., Aengenheister, L., Hansen, S. S. K., Hougaard, K. S. & Buerki-Thurnherr,
T. Recent insights on indirect mechanisms in developmental toxicity of nanomaterials.
nancy132. Recognizing and exploiting these similarities can be a pivotal
Part. Fibre Toxicol. 17, 31 (2020).
step towards the development of delivery technologies for women’s 18. Campaña-Seoane, M. et al. Vaginal residence and pharmacokinetic preclinical study
health applications, addressing many of the challenges that limit their of topical vaginal mucoadhesive W/S emulsions containing ciprofloxacin. Int. J. Pharm.
554, 276–283 (2019).
clinical translation (Box 1).
19. Hoang, T. et al. Development of a mucoinert progesterone nanosuspension for safer and
Key barriers to the clinical translation of delivery systems for more effective prevention of preterm birth. J. Control. Rel. 295, 74–86 (2019).
women’s health applications also include systemic and societal chal- 20. Bulletti, C. et al. Vaginal drug delivery: the first uterine pass effect. Ann. N. Y. Acad. Sci.
828, 285–290 (1997).
lenges, such as the exclusion of pregnant women from clinical trials,
21. Bulletti, C. et al. Targeted drug delivery in gynaecology: the first uterine pass effect.
the limited funding designated explicitly for women’s health research, Hum. Reprod. 12, 1073–1079 (1997).
and the racial disparities for many women-specific disorders (Box 1). 22. Cicinelli, E. et al. Plasma concentrations of progesterone are higher in the uterine artery
than in the radial artery after vaginal administration of micronized progesterone in an
Therefore, in addition to designing, optimizing and evaluating delivery oil-based solution to postmenopausal women. Fertil. Steril. 69, 471–473 (1998).
technologies, community members and advocates must play a role in 23. McCracken, J. M. et al. Animal models and alternatives in vaginal research: a comparative
addressing these systemic barriers. review. Reprod. Sci. 28, 1759–1773 (2021).
24. Vermani, K. & Garg, S. The scope and potential of vaginal drug delivery. Pharm. Sci.
Perhaps one of the most successful clinical demonstrations of Technol. Today 3, 359–364 (2000).
a delivery technology in the field of women’s health research is the 25. Maestrelli, F., Jug, M., Cirri, M., Kosalec, I. & Mura, P. Characterization and microbiological
growing evidence of the efficacy of LNP-mediated mRNA vaccines for evaluation of chitosan-alginate microspheres for cefixime vaginal administration.
Carbohydr. Polym. 192, 176–183 (2018).
COVID-19 in pregnant and lactating women168,169, with demonstration 26. Pisano, S. et al. Liquid crystal delivery of ciprofloxacin to treat infections of the female
of potent maternal immune responses and the potential of transpla- reproductive tract. Biomed. Microdevices 21, 36 (2019).
cental antibody transfer that benefits the fetus. Therefore, LNPs may 27. Alqahtani, F. et al. Antibacterial activity of chitosan nanoparticles against pathogenic
N. gonorrhoea. Int. J. Nanomed. 15, 7877–7887 (2020).
also enable the delivery of other drugs and cargo during pregnancy. 28. Rowley, J. et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence
However, thorough and long-term studies evaluating the safety of and incidence estimates, 2016. Bull. World Health Organ. 97, 548–562P (2019).
the COVID-19 vaccines in pregnant women, particularly in regard to 29. Palmeira-de-Oliveira, R., Palmeira-de-Oliveira, A. & Martinez-de-Oliveira, J. New
strategies for local treatment of vaginal infections. Adv. Drug Deliv. Rev. 92, 105–122
chronic effects from prenatal exposure to foreign biomaterials, will (2015).
be essential to better understand direct and indirect effects on fetal 30. Shapiro, R. L. et al. In vitro and ex vivo models for evaluating vaginal drug delivery
development. Preclinical research and collaboration between bioen- systems. Adv. Drug Deliv. Rev. 191, 114543 (2022).
31. Tuğcu-Demiröz, F. et al. Development and characterization of chitosan nanoparticles
gineers, clinicians, patients, regulatory officials and advocates will be loaded nanofiber hybrid system for vaginal controlled release of benzydamine.
required to develop and translate therapeutic delivery technologies Eur. J. Pharm. Sci. 161, 105801 (2021).
for women’s health. 32. Jøraholmen, M. W., Basnet, P., Tostrup, M. J., Moueffaq, S. & Škalko-Basnet, N. Localized
therapy of vaginal infections and inflammation: liposomes-in-hydrogel delivery system
for polyphenols. Pharmaceutics 11, 53 (2019).
Published online: xx xx xxxx 33. Abd Ellah, N. H. et al. Efficacy of ketoconazole gel-flakes in treatment of vaginal
candidiasis: formulation, in vitro and clinical evaluation. Int. J. Pharm. 567, 118472
(2019).
References 34. Calvo, N. L. et al. Chitosan-hydroxypropyl methylcellulose tioconazole films: a promising
1. Riley, R. S., June, C. H., Langer, R. & Mitchell, M. J. Delivery technologies for cancer alternative dosage form for the treatment of vaginal candidiasis. Int. J. Pharm. 556,
immunotherapy. Nat. Rev. Drug Discov. 18, 175–196 (2019). 181–191 (2019).
2. Kauffman, K. J., Webber, M. J. & Anderson, D. G. Materials for non-viral intracellular 35. Deshkar, S. S. & Palve, V. K. Formulation and development of thermosensitive
delivery of messenger RNA therapeutics. J. Control. Rel. 240, 227–234 (2016). cyclodextrin-based in situ gel of voriconazole for vaginal delivery. J. Drug Deliv.
3. Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in Sci. Technol. 49, 277–285 (2019).
vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). 36. Salah, S., Awad, G. E. A. & Makhlouf, A. I. A. Improved vaginal retention and enhanced
4. Mirin, A. A. Gender disparity in the funding of diseases by the U.S. National Institutes antifungal activity of miconazole microsponges gel: formulation development and
of Health. J. Womens Health 30, 956–963 (2021). in vivo therapeutic efficacy in rats. Eur. J. Pharm. Sci. 114, 255–266 (2018).
5. Nijjar, S. et al. Participation in clinical trials improves outcomes in women’s health: 37. Querobino, S. M. et al. Sodium alginate in oil-poloxamer organogels for intravaginal drug
a systematic review and meta-analysis. BJOG 124, 863–871 (2017). delivery: influence on structural parameters, drug release mechanisms, cytotoxicity and
6. Steinberg, J. R. et al. Early discontinuation, results reporting, and publication of in vitro antifungal activity. Mater. Sci. Eng. C. 99, 1350–1361 (2019).
gynecology clinical trials from 2007 to 2020. Obstet. Gynecol. 139, 821–831 (2022). 38. Martínez-Pérez, B. et al. Controlled-release biodegradable nanoparticles: from
7. Sultana, A., Zare, M., Thomas, V., Kumar, T. S. S. & Ramakrishna, S. Nano-based drug preparation to vaginal applications. Eur. J. Pharm. Sci. 115, 185–195 (2018).
delivery systems: conventional drug delivery routes, recent developments and future 39. Li, W.-Z. et al. Propylene glycol-embodying deformable liposomes as a novel drug delivery
prospects. Med. Drug Discov. 15, 100134 (2022). carrier for vaginal fibrauretine delivery applications. J. Control. Rel. 226, 107–114 (2016).
8. Swingle, K. L., Hamilton, A. G. & Mitchell, M. J. Lipid nanoparticle-mediated delivery 40. Cautela, M. P., Moshe, H., Sosnik, A., Sarmento, B. & das Neves, J. Composite films
of mRNA therapeutics and vaccines. Trends Mol. Med. 27, 616–617 (2021). for vaginal delivery of tenofovir disoproxil fumarate and emtricitabine. Eur. J. Pharm.
9. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Biopharm. 138, 3–10 (2019).
Drug Discov. https://doi.org/10.1038/s41573-020-0090-8 (2020). 41. Crakes, K. R. et al. Efficacy of silk fibroin biomaterial vehicle for in vivo mucosal delivery
10. Diaz, S. et al. A five-year clinical trial of levonorgestrel silastic implants (NorplantTM). of Griffithsin and protection against HIV and SHIV infection ex vivo. J. Int. AIDS Soc. 23,
Contraception 25, 447–456 (1982). e25628 (2020).

Nature Reviews Bioengineering

Review article

42. Cunha-Reis, C. et al. Nanoparticles-in-film for the combined vaginal delivery of anti-HIV 72. Moses, A. S. et al. Nanoparticle-based platform for activatable fluorescence imaging and
microbicide drugs. J. Control. Rel. 243, 43–53 (2016). photothermal ablation of endometriosis. Small 16, 1906936 (2020).
43. Ramyadevi, D., Rajan, K. S., Vedhahari, B. N., Ruckmani, K. & Subramanian, N. 73. Wang, C. et al. Silencing of MEF2D by siRNA loaded selenium nanoparticles for ovarian
Heterogeneous polymer composite nanoparticles loaded in situ gel for controlled cancer therapy. Int. J. Nanomed. 15, 9759–9770 (2020).
release intra-vaginal therapy of genital herpes. Colloids Surf. B 146, 260–270 (2016). 74. Pan, Q. et al. Tumor-targeting polycaprolactone nanoparticles with codelivery of paclitaxel
44. Yang, H. et al. Design of poly(lactic-co-glycolic acid) (PLGA) nanoparticles for vaginal and IR780 for combinational therapy of drug-resistant ovarian cancer. ACS Biomater.
co-delivery of Griffithsin and Dapivirine and their synergistic effect for HIV prophylaxis. Sci. Eng. 6, 2175–2185 (2020).
Pharmaceutics 11, 184 (2019). 75. Domínguez-Ríos, R. et al. Cisplatin-loaded PLGA nanoparticles for HER2 targeted ovarian
45. Kim, S. et al. Design and development of pH-responsive polyurethane membranes for cancer therapy. Colloids Surf. B 178, 199–207 (2019).
intravaginal release of nanomedicines. Acta Biomater. 82, 12–23 (2018). 76. Michy, T. et al. Verteporfin-loaded lipid nanoparticles improve ovarian cancer
46. Wang, J. et al. A thermosensitive gel based on w1/o/w2 multiple microemulsions for the photodynamic therapy in vitro and in vivo. Cancers 11, 1760 (2019).
vaginal delivery of small nucleic acid. Drug Deliv. 26, 168–178 (2019). 77. Zaman, M. S. et al. Curcumin nanoformulation for cervical cancer treatment. Sci. Rep. 6,
47. Woodrow, K. A. et al. Intravaginal gene silencing using biodegradable polymer 20051 (2016).
nanoparticles densely loaded with small-interfering RNA. Nat. Mater. 8, 526–533 78. Liu, B. et al. Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid
(2009). nanoparticles with synergistic antitumor activity against cervical cancer. Int. J. Nanomed.
This article reports a new technique for small interfering RNA loading into polymeric 12, 955–968 (2017).
nanoparticles formulated with FDA-approved materials for gene silencing in the mouse 79. Xia, Y. et al. Functionalized selenium nanoparticles for targeted siRNA delivery silence
reproductive tract following intravaginal administration. Derlin1 and promote antitumor efficacy against cervical cancer. Drug Deliv. 27, 15–25
48. Steinbach, J. M., Weller, C. E., Booth, C. J. & Saltzman, W. M. Polymer nanoparticles (2020).
encapsulating siRNA for treatment of HSV-2 genital infection. J. Control. Rel. 162, 102–110 80. Ci, L. et al. Enhanced delivery of imatinib into vaginal mucosa via a new positively
(2012). charged nanocrystal-loaded in situ hydrogel formulation for treatment of cervical
49. Ariza-Sáenz, M. et al. Design, characterization, and biopharmaceutical behavior of cancer. Pharmaceutics 11, 15 (2019).
nanoparticles loaded with an HIV-1 fusion inhibitor peptide. Mol. Pharm. 15, 5005–5018 81. Zhai, J. et al. Paclitaxel-loaded self-assembled lipid nanoparticles as targeted drug
(2018). delivery systems for the treatment of aggressive ovarian cancer. ACS Appl. Mater.
50. Gong, T., Patel, S. K., Parniak, M. A., Ballou, B. & Rohan, L. C. Nanocrystal formulation Interfaces 10, 25174–25185 (2018).
improves vaginal delivery of CSIC for HIV prevention. AAPS PharmSciTech 20, 286 (2019). 82. Yi, Y. et al. Targeted systemic delivery of siRNA to cervical cancer model using cyclic
51. Orłowski, P. et al. Antiviral activity of tannic acid modified silver nanoparticles: potential RGD-installed unimer polyion complex-assembled gold nanoparticles. J. Control. Release
to activate immune response in herpes genitalis. Viruses 10, 524 (2018). 244, 247–256 (2016).
52. Hajj, K. A. et al. Branched-tail lipid nanoparticles potently deliver mRNA in vivo due to 83. Xu, G. et al. Robust aptamer–polydopamine-functionalized M-PLGA–TPGS nanoparticles
enhanced ionization at endosomal pH. Small 15, 1805097 (2019). for targeted delivery of docetaxel and enhanced cervical cancer therapy. Int. J. Nanomed.
53. Heyes, J., Palmer, L., Bremner, K. & MacLachlan, I. Cationic lipid saturation influences 11, 2953–2965 (2016).
intracellular delivery of encapsulated nucleic acids. J. Control. Rel. 107, 276–287 (2005). 84. Byeon, Y. et al. CD44-targeting PLGA nanoparticles incorporating paclitaxel and
54. Cu, Y. & Saltzman, W. M. Controlled surface modification with poly(ethylene)glycol FAK siRNA overcome chemoresistance in epithelial ovarian cancer. Cancer Res. 78,
enhances diffusion of PLGA nanoparticles in human cervical mucus. Mol. Pharm. 6, 6247–6256 (2018).
173–181 (2009). 85. Correa, S. et al. Tuning nanoparticle interactions with ovarian cancer through layer-by-layer
55. Cu, Y., Booth, C. J. & Saltzman, W. M. In vivo distribution of surface-modified PLGA modification of surface chemistry. ACS Nano 14, 2224–2237 (2020).
nanoparticles following intravaginal delivery. J. Control. Rel. 156, 258–264 (2011). This article reports the identification of layer-by-layer nanoparticle formulations with
56. Ensign, L. M. et al. Mucus-penetrating nanoparticles for vaginal drug delivery protect specificity for ovarian cancer and demonstrates in vivo tumour-homing in a murine
against herpes simplex virus. Sci. Transl. Med. 4, 138ra79–138ra79 (2012). model of metastatic ovarian cancer.
This article reports the design of mucus-penetrating nanoparticles for uniform drug 86. Mensah, L. B. et al. Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP
delivery to the vaginal epithelium, and more effective protection against herpes inhibitors for platinum-based drug resistance therapy in ovarian cancer. Bioeng. Transl.
simplex virus 2 challenge in mice than the soluble drug. Med. 4, e10131 (2019).
57. Jøraholmen, M. W., Basnet, P., Acharya, G. & Škalko-Basnet, N. PEGylated liposomes for 87. Cheng, C., Meng, Y., Zhang, Z., Li, Y. & Zhang, Q. Tumoral acidic pH-responsive cis-
topical vaginal therapy improve delivery of interferon alpha. Eur. J. Pharm. Biopharm. 113, diaminodichloroplatinum-incorporated Cy5.5-PEG-g-A-HA nanoparticles for targeting
132–139 (2017). delivery of CDDP against cervical cancer. ACS Appl. Mater. Interfaces 10, 26882–26892
58. Krogstad, E. A. et al. Nanoparticle-releasing nanofiber composites for enhanced in vivo (2018).
vaginal retention. Biomaterials 144, 1–16 (2017). 88. Shen, W. et al. Sustained codelivery of cisplatin and paclitaxel via an injectable prodrug
59. Mohideen, M. et al. Degradable bioadhesive nanoparticles for prolonged intravaginal hydrogel for ovarian cancer treatment. ACS Appl. Mater. Interfaces 9, 40031–40046
delivery and retention of Elvitegravir. Biomaterials 144, 144–154 (2017). (2017).
60. Simón-Gracia, L. et al. Homing peptide-based targeting of tenascin-C and fibronectin in 89. Sun, B. et al. Intraperitoneal chemotherapy of ovarian cancer by hydrogel depot of
endometriosis. Nanomaterials 11, 3257 (2021). paclitaxel nanocrystals. J. Control. Rel. 235, 91–98 (2016).
61. Liu, Q. et al. Evaluation of PLGA containing anti-CTLA4 inhibited endometriosis 90. Jamal, A. et al. Identification of anti-cancer potential of doxazocin: loading into chitosan
progression by regulating CD4+CD25+Treg cells in peritoneal fluid of mouse based biodegradable hydrogels for on-site delivery to treat cervical cancer. Mater. Sci.
endometriosis model. Eur. J. Pharm. Sci. 96, 542–550 (2017). Eng. C. 82, 102–109 (2018).
62. Boroumand, S., Hosseini, S., Pashandi, Z., Faridi-Majidi, R. & Salehi, M. Curcumin-loaded 91. Nash, A. M. et al. Clinically translatable cytokine delivery platform for eradication of
nanofibers for targeting endometriosis in the peritoneum of a mouse model. J. Mater. Sci. intraperitoneal tumors. Sci. Adv. 8, eabm1032 (2022).
Mater Med. 31, 8 (2019). This article reports the development of an interleukin-2 cytokine factory with alginate
63. Siddiqa, A. J. et al. Preparation of letrozole dispersed pHEMA/AAm-g-LDPE drug release microcapsules for reducing ovarian cancer tumour burden following intraperitoneal
system: in-vitro release kinetics for the treatment of endometriosis. Colloids Surf. B 179, administration.
445–452 (2019). 92. Nash, A. M. et al. Activation of adaptive and innate immune cells via localized
64. Egorova, A. et al. Anti-angiogenic treatment of endometriosis via anti-VEGFA siRNA Interleukin-2 cytokine factories eradicates mesothelioma tumors. Clin. Cancer Res.
delivery by means of peptide-based carrier in a rat subcutaneous model. Gene Ther. 25, https://doi.org/10.1158/1078-0432.CCR-22-1493 (2022).
548–555 (2018). 93. Wang, X. et al. Vaginal delivery of mucus-penetrating organic nanoparticles for photothermal
65. Liang, Z. et al. miR-200c suppresses endometriosis by targeting MALAT1 in vitro and therapy against cervical intraepithelial neoplasia in mice. J. Mater. Chem. B 7, 4528–4537
in vivo. Stem Cell Res. Ther. 8, 251 (2017). (2019).
66. Yuan, M. et al. Effect of A-317491 delivered by glycolipid-like polymer micelles on 94. Jalalvandi, E. & Shavandi, A. In situ-forming and pH-responsive hydrogel based on
endometriosis pain. Int. J. Nanomed. 12, 8171–8183 (2017). chitosan for vaginal delivery of therapeutic agents. J. Mater. Sci. Mater Med. 29, 158
67. Zhao, M.-D. et al. Hyaluronic acid reagent functional chitosan-PEI conjugate with AQP2-siRNA (2018).
suppressed endometriotic lesion formation. Int. J. Nanomed. 11, 1323–1336 (2016). 95. Risnayanti, C., Jang, Y.-S., Lee, J. & Ahn, H. J. PLGA nanoparticles co-delivering MDR1
68. Kiisholts, K. et al. Cell-penetrating peptide and siRNA-mediated therapeutic effects on and BCL2 siRNA for overcoming resistance of paclitaxel and cisplatin in recurrent or
endometriosis and cancer in vitro models. Pharmaceutics 13, 1618 (2021). advanced ovarian cancer. Sci. Rep. 8, 7498 (2018).
69. Bedin, A. et al. Nanotechnology for the treatment of deep endometriosis: uptake 96. Zhang, Q. et al. Photoactivatable prodrug-backboned polymeric nanoparticles for
of lipid core nanoparticles by LDL receptors in endometriotic foci. Clinics 74, e989 efficient light-controlled gene delivery and synergistic treatment of platinum-resistant
(2019). ovarian cancer. Nano Lett. 20, 3039–3049 (2020).
70. Park, Y. et al. Targeted nanoparticles with high heating efficiency for the treatment of 97. Bertucci, A. et al. Tumor-targeting, microRNA-silencing porous silicon nanoparticles for
endometriosis with systemically delivered magnetic hyperthermia. Small 18, 2107808 ovarian cancer therapy. ACS Appl. Mater. Interfaces 11, 23926–23937 (2019).
(2022). 98. Zhang, X.-F., Yan, Q., Shen, W. & Gurunathan, S. Trichostatin A enhances the apoptotic
71. Zhang, H. et al. Hyaluronic acid-modified magnetic iron oxide nanoparticles for MR potential of palladium nanoparticles in human cervical cancer cells. Int. J. Mol. Sci. 17,
imaging of surgically induced endometriosis model in rats. PLoS ONE 9, e94718 (2014). 1354 (2016).

Nature Reviews Bioengineering

Review article

99. Dunk, C. et al. Failure of decidualization and maternal immune tolerance underlies 130. Alfaifi, A. A. et al. Megalin-targeting liposomes for placental drug delivery. J. Control. Rel.
uterovascular resistance in intra uterine growth restriction. Front. Endocrinol. 10, 160 324, 366–378 (2020).
(2019). 131. Li, L. et al. Nanoparticle-mediated simultaneous downregulation of placental Nrf2
100. Kim, C. J., Romero, R., Chaemsaithong, P. & Kim, J.-S. Chronic inflammation of the and sFlt1 improves maternal and fetal outcomes in a preeclampsia mouse model.
placenta: definition, classification, pathogenesis, and clinical significance. Am. J. Obstet. ACS Biomater. Sci. Eng. 6, 5866–5873 (2020).
Gynecol. 213, S53–S69 (2015). 132. King, A. et al. Tumor-homing peptides as tools for targeted delivery of payloads to the
101. Knöfler, M. et al. Human placenta and trophoblast development: key molecular placenta. Sci. Adv. 2, e1600349 (2021).
mechanisms and model systems. Cell. Mol. Life Sci. 76, 3479–3496 (2019). This article reports the design of tumour-homing peptide-targeted liposomes for
102. Thompson, L. P., Pence, L., Pinkas, G., Song, H. & Telugu, B. P. Placental hypoxia during in vivo accumulation in the placenta and demonstrates that delivery of insulin-like
early pregnancy causes maternal hypertension and placental insufficiency in the hypoxic growth factor 2 can improve fetal weight distribution in a murine model of fetal growth
guinea pig model. Biol. Reprod. 95, 128 (2016). restriction.
103. Aengenheister, L. et al. An advanced human in vitro co-culture model for translocation 133. Ellah, N. A. et al. Development of non-viral, trophoblast-specific gene delivery for placental
studies across the placental barrier. Sci. Rep. 8, 5388 (2018). therapy. PLoS ONE 10, e0140879 (2015).
104. Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. 134. Young, R. E. et al. Lipid nanoparticle composition drives mRNA delivery to the placenta.
J. Med. 350, 672–683 (2004). Preprint at bioRxiv https://www.biorxiv.org/content/10.1101/2022.12.22.521490v1 (2022).
105. Umapathy, A., Chamley, L. W. & James, J. L. Reconciling the distinct roles of angiogenic/ 135. Swingle, K. L. et al. Ionizable lipid nanoparticles for in vivo mRNA delivery to the placenta
anti-angiogenic factors in the placenta and maternal circulation of normal and pathological during pregnancy. J. Am. Chem. Soc. https://doi.org/10.1021/jacs.2c12893 (2023).
pregnancies. Angiogenesis 23, 105–117 (2020). 136. Sanghavi, M. & Rutherford, J. D. Cardiovascular physiology of pregnancy. Circulation 130,
106. Whigham, C.-A. et al. The untapped potential of placenta-enriched molecules for 1003–1008 (2014).
diagnostic and therapeutic development. Placenta 84, 28–31 (2019). 137. Frederiksen, M. C. Physiologic changes in pregnancy and their effect on drug disposition.
107. Dodd, A. et al. Conjugation to PEG as a strategy to limit the uptake of drugs by the Semin. Perinatol. 25, 120–123 (2001).
placenta: potential applications for drug administration in pregnancy. Mol. Pharm. 19, 138. Yu, J., Jia, J., Guo, X., Chen, R. & Feng, L. Modulating circulating sFlt1 in an animal model
345–353 (2022). of preeclampsia using PAMAM nanoparticles for siRNA delivery. Placenta https://doi.org/
108. Ali, S. et al. Formulation effects on paclitaxel transfer and uptake in the human placenta. 10.1016/j.placenta.2017.07.360 (2017).
Nanomedicine 33, 102354 (2021). 139. McCarthy, F. P., Kingdom, J. C., Kenny, L. C. & Walsh, S. K. Animal models of preeclampsia;
109. Joshi, M. D. Drug delivery during pregnancy: how can nanomedicine be used? Ther. Deliv. uses and limitations. Placenta 32, 413–419 (2011).
8, 1023–1025 (2017). 140. Wilson, R. L. et al. Nanoparticle mediated increased insulin-like growth factor 1
110. Kuna, M., Waller, J. P., Logue, O. C. & Bidwell, G. L. Polymer size affects biodistribution expression enhances human placenta syncytium function. Placenta https://doi.org/
and placental accumulation of the drug delivery biopolymer elastin-like polypeptide in 10.1016/j.placenta.2020.02.006 (2020).
a rodent pregnancy model. Placenta 72–73, 20–27 (2018). 141. Beards, F., Jones, L. E., Charnock, J., Forbes, K. & Harris, L. K. Placental homing peptide-
111. Aengenheister, L. et al. Gold nanoparticle distribution in advanced in vitro and ex vivo microRNA inhibitor conjugates for targeted enhancement of intrinsic placental growth
human placental barrier models. J. Nanobiotechnol. 16, 79 (2018). signaling. Theranostics 7, 2940–2955 (2017).
112. Muoth, C. et al. Impact of particle size and surface modification on gold nanoparticle 142. Cureton, N. et al. Selective targeting of a novel vasodilator to the uterine vasculature to
penetration into human placental microtissues. Nanomedicine 12, 1119–1133 (2017). treat impaired uteroplacental perfusion in pregnancy. Theranostics 7, 3715–3731 (2017).
113. Irvin-Choy, N. S., Nelson, K. M., Dang, M. N., Gleghorn, J. P. & Day, E. S. Gold nanoparticle 143. Renshall, L. J. et al. Targeted delivery of epidermal growth factor to the human placenta
biodistribution in pregnant mice following intravenous administration varies with to treat fetal growth restriction. Pharmaceutics 13, 1778 (2021).
gestational age. Nanomedicine 36, 102412 (2021). 144. Li, L. et al. Trophoblast-targeted nanomedicine modulates placental sFLT1 for
114. Ho, D. et al. Maternal–placental–fetal biodistribution of multimodal polymeric preeclampsia treatment. Front. Bioeng. Biotechnol. 8, 64 (2020).
nanoparticles in a pregnant rat model in mid and late gestation. Sci. Rep. 7, 2866 145. Ullrich, S. J. et al. Nanoparticles for delivery of agents to fetal lungs. Acta Biomaterialia
(2017). 123, 346–353 (2021).
115. Juch, H. et al. Dendritic polyglycerol nanoparticles show charge dependent bio-distribution 146. Riley, R. S. et al. Ionizable lipid nanoparticles for in utero mRNA delivery. Sci. Adv. 7,
in early human placental explants and reduce hCG secretion. Nanotoxicology 12, 90–103 eaba1028 (2021).
(2018). This article reports the identification of ionizable lipid nanoparticle formulations
116. Zhang, B. et al. Placenta-specific drug delivery by trophoblast-targeted nanoparticles for mRNA delivery to the fetal liver, lungs and intestines following vitelline vein
in mice. Theranostics 8, 2765–2781 (2018). administration in murine fetuses.
117. Yang, H., Du, L., Wu, G., Wu, Z. & Keelan, J. A. Murine exposure to gold nanoparticles 147. Ricciardi, A. S. et al. In utero nanoparticle delivery for site-specific genome editing.
during early pregnancy promotes abortion by inhibiting ectodermal differentiation. Nat. Commun. 9, 2481 (2018).
Mol. Med. 24, 62 (2018). This article reports safe and effective in utero gene editing in murine β-thalassemia
118. Georgiades, P., Ferguson-Smith, A. C. & Burton, G. J. Comparative developmental fetuses following vitelline vein administration of polymeric nanoparticles encapsulating
anatomy of the murine and human definitive placentae. Placenta 23, 3–19 (2002). peptide nucleic acids and donor DNAs.
119. Hemberger, M., Hanna, C. W. & Dean, W. Mechanisms of early placental development 148. Freedman-Weiss, M. R. et al. Engineering alginate microparticles for optimized accumulation
in mouse and humans. Nat. Rev. Genet. 21, 27–43 (2020). in fetal rat myelomeningocele. J. Pediatr. Surg. https://doi.org/10.1016/j.jpedsurg.2021.03.060
120. Furukawa, S., Kuroda, Y. & Sugiyama, A. A comparison of the histological structure of the (2021).
placenta in experimental animals. J. Toxicol. Pathol. 27, 11–18 (2014). 149. Adzick, N. S. et al. A randomized trial of prenatal versus postnatal repair of
121. Raia, N. R., Bakaysa, S. L., Ghezzi, C. E., House, M. D. & Kaplan, D. L. Ex vivo pregnant- myelomeningocele. N. Engl. J. Med. 364, 993–1004 (2011).
like tissue model to assess injectable hydrogel for preterm birth prevention. J. Biomed. 150. Swingle, K. L. et al. Amniotic fluid stabilized lipid nanoparticles for in utero intra-amniotic
Mater. Res. B 108, 468–474 (2020). mRNA delivery. J. Control. Rel. 341, 616–633 (2022).
122. Refuerzo, J. S. et al. Uterus-targeted liposomes for preterm labor management: studies in 151. Palanki, R., Peranteau, W. H. & Mitchell, M. J. Delivery technologies for in utero gene
pregnant mice. Sci. Rep. 6, 34710 (2016). therapy. Adv. Drug Deliv. Rev. 169, 51–62 (2021).
123. Brown, J. E., Partlow, B. P., Berman, A. M., House, M. D. & Kaplan, D. L. Injectable silk-based 152. Alapati, D. et al. In utero gene editing for monogenic lung disease. Sci. Transl. Med. 11,
biomaterials for cervical tissue augmentation: an in vitro study. Am. J. Obstet. Gynecol. eaav8375 (2019).
214, 118.e1–118.e9 (2016). 153. Almeida-Porada, G. et al. In utero gene therapy consensus statement from the IFeTIS.
124. Lei, J. et al. Maternal dendrimer-based therapy for inflammation-induced preterm birth Mol. Ther. 27, 705–707 (2019).
and perinatal brain injury. Sci. Rep. 7, 6106 (2017). 154. Cornford, E. M. et al. Non-invasive gene targeting to the fetal brain after intravenous
125. Zhang, Y., Raia, N., Peterson, A., Kaplan, D. L. & House, M. Injectable silk-based hydrogel administration and transplacental transfer of plasmid DNA using PEGylated
as an alternative to cervical cerclage: a rabbit study. Tissue Eng. A 26, 379–386 (2020). immunoliposomes. J. Drug Target. 24, 58–67 (2016).
126. Zierden, H. C. et al. Enhanced drug delivery to the reproductive tract using nanomedicine 155. Nakamura, S. et al. Transplacental delivery of genome editing components causes
reveals therapeutic options for prevention of preterm birth. Sci. Transl. Med. 13, eabc6245 mutations in embryonic cardiomyocytes of mid-gestational murine fetuses. IUBMB Life
(2021). 71, 835–844 (2019).
This article reports the use of mucoinert nanosuspensions of histone deacetylase 156. Mazzone, L. et al. Bioengineering and in utero transplantation of fetal skin in the sheep
inhibitors for preventing preterm birth and promoting birth of live pups with model: A crucial step towards clinical application in human fetal spina bifida repair.
neurotypical development in a murine model of intrauterine inflammation. J. Tissue Eng. Regen. Med. 14, 58–65 (2020).
127. Murphy, C. C., Cirillo, P. M., Krigbaum, N. Y. & Cohn, B. A. In utero exposure to 157. Farrelly, J. S. et al. Alginate microparticles loaded with basic fibroblast growth factor induce
17α-hydroxyprogesterone caproate and risk of cancer in offspring. Am. J. Obstet. tissue coverage in a rat model of myelomeningocele. J. Pediatr. Surg. 54, 80–85 (2019).
Gynecol. 226, 132.e1–132.e14 (2022). 158. Papanna, R. et al. Cryopreserved human umbilical cord patch for in-utero spina bifida
128. Chang, C. Y. et al. Withdrawing approval of Makena — a proposal from the FDA Center for repair. Ultrasound Obstet. Gynecol. 47, 168–176 (2016).
Drug Evaluation and Research. N. Engl. J. Med. 383, e131 (2020). 159. Mann, L. K. et al. Cryopreserved human umbilical cord versus acellular dermal matrix
129. Paul, J. W. et al. Drug delivery to the human and mouse uterus using immunoliposomes patches for in utero fetal spina bifida repair in a pregnant rat model. J. Neurosurg. Spine
targeted to the oxytocin receptor. Am. J. Obstet. Gynecol. 216, 283.e1–283.e14 (2017). 32, 321–331 (2019).

Nature Reviews Bioengineering

Review article

160. Oria, M., Tatu, R. R., Lin, C.-Y. & Peiro, J. L. In vivo evaluation of novel PLA/PCL polymeric 188. Camunas-Soler, J. et al. Predictive RNA profiles for early and very early spontaneous
patch in rats for potential spina bifida coverage. J. Surg. Res. 242, 62–69 (2019). preterm birth. Am. J. Obstet. Gynecol. 227, 72.e1–72.e16 (2022).
161. Bardill, J. R., Park, D. & Marwan, A. I. Improved coverage of mouse myelomeningocele 189. Rasmussen, M. et al. RNA profiles reveal signatures of future health and disease in
with a mussel inspired reverse thermal gel. J. Surg. Res. 251, 262–274 (2020). pregnancy. Nature 601, 422–427 (2022).
162. Bardill, J. et al. An injectable reverse thermal gel for minimally invasive coverage of 190. Ngo, T. T. M. et al. Noninvasive blood tests for fetal development predict gestational age
mouse myelomeningocele. J. Surg. Res. 235, 227–236 (2019). and preterm delivery. Science 360, 1133–1136 (2018).
163. Watanabe, M. et al. Complete tissue coverage achieved by scaffold-based tissue 191. Sewell, C. A. et al. Scientific, ethical, and legal considerations for the inclusion of pregnant
engineering in the fetal sheep model of myelomeningocele. Biomaterials 76, 133–143 people in clinical trials. Am. J. Obstet. Gynecol. https://doi.org/10.1016/j.ajog.2022.07.037
(2016). (2022).
164. Vanover, M. et al. High density placental mesenchymal stromal cells provide neuronal 192. Ren, Z., Bremer, A. A. & Pawlyk, A. C. Drug development research in pregnant and
preservation and improve motor function following in utero treatment of ovine lactating women. Am. J. Obstet. Gynecol. 225, 33–42 (2021).
myelomeningocele. J. Pediatr. Surg. 54, 75–79 (2019). 193. Mazer-Amirshahi, M., Samiee-Zafarghandy, S., Gray, G. & van den Anker, J. N. Trends in
165. Li, X. et al. Application potential of bone marrow mesenchymal stem cell (BMSCs) based pregnancy labeling and data quality for US-approved pharmaceuticals. Am. J. Obstet.
tissue-engineering for spinal cord defect repair in rat fetuses with spina bifida aperta. Gynecol. 211, 690.e1–690.e11 (2014).
J. Mater. Sci. Mater Med. 27, 77 (2016). 194. Couzin-Frankel, J. The pregnancy gap. Science 375, 1216–1220 (2022).
166. Dasargyri, A., Reichmann, E. & Moehrlen, U. Bio-engineering of fetal cartilage for in utero 195. Carter, E. B. & Mazzoni, S. E. A paradigm shift to address racial inequities in perinatal
spina bifida repair. Pediatr. Surg. Int. 36, 25–31 (2020). healthcare. Am. J. Obstet. Gynecol. 224, 359–361 (2021).
167. Barenholz, Y. Doxil® — the first FDA-approved nano-drug: lessons learned. J. Control. Rel. 196. Phillippe, M. Telomeres, oxidative stress, and timing for spontaneous term and preterm
160, 117–134 (2012). labor. Am. J. Obstet. Gynecol. 227, 148–162 (2022).
168. Beharier, O. et al. Efficient maternal to neonatal transfer of antibodies against SARS-CoV-2 197. Lacroix, G., Gouyer, V., Gottrand, F. & Desseyn, J.-L. The cervicovaginal mucus barrier.
and BNT162b2 mRNA COVID-19 vaccine. J. Clin. Invest. 131, e150319 (2021). Int. J. Mol. Sci. 21, 8266 (2020).
169. Prahl, M. et al. Evaluation of transplacental transfer of mRNA vaccine products and 198. France, M., Alizadeh, M., Brown, S., Ma, B. & Ravel, J. Towards a deeper understanding of
functional antibodies during pregnancy and infancy. Nat. Commun. 13, 4422 (2022). the vaginal microbiota. Nat. Microbiol. 7, 367–378 (2022).
170. Yang, S., Traore, Y., Jimenez, C. & Ho, E. A. Autophagy induction and PDGFR-β knockdown 199. Saunders, P. T. K. in Animal Models for Endometriosis: Evolution, Utility and Clinical
by siRNA-encapsulated nanoparticles reduce Chlamydia trachomatis infection. Sci. Rep. Relevance (ed. Sharpe-Timms, K. L.) 99–111 (Springer, 2020).
9, 1306 (2019). 200. Laganà, A. S. et al. Translational animal models for endometriosis research: a long and
171. Köllner, S. et al. Self-emulsifying drug delivery systems: design of a novel vaginal windy road. Ann. Transl. Med. 6, 431 (2018).
delivery system for curcumin. Eur. J. Pharm. Biopharm. 115, 268–275 (2017). 201. Bobbs, A. S., Cole, J. M. & Dahl, K. D. C. Emerging and evolving ovarian cancer animal
172. Luiz, M. T. et al. In vitro evaluation of folate-modified PLGA nanoparticles containing models. Cancer Growth Metastasis 8, 29–36 (2015).
paclitaxel for ovarian cancer therapy. Mater. Sci. Eng. C. 105, 110038 (2019). 202. Mitchell, L. E. et al. Spina bifida. Lancet 364, 1885–1895 (2004).
173. Lv, F. et al. Enhanced mucosal penetration and efficient inhibition efficacy against 203. Ehlers, K., Stürje, H., Merker, H.-J. & Nau, H. Valproic acid-induced spina bifida: a mouse
cervical cancer of PEGylated docetaxel nanocrystals by TAT modification. J. Control. Rel. model. Teratology 45, 145–154 (1992).
336, 572–582 (2021). 204. Meuli, M. et al. Creation of myelomeningocele in utero: a model of functional damage
174. Hu, R. et al. Core–shell magnetic gold nanoparticles for magnetic field-enhanced from spinal cord exposure in fetal sheep. J. Pediatr. Surg. 30, 1028–1033 (1995).
radio-photothermal therapy in cervical cancer. Nanomaterials 7, 111 (2017). 205. Joyeux, L. et al. Validation of the fetal lamb model of spina bifida. Sci. Rep. 9, 9327 (2019).
175. You, L., Liu, X., Fang, Z., Xu, Q. & Zhang, Q. Synthesis of multifunctional Fe3O4@PLGA-PEG
nano-niosomes as a targeting carrier for treatment of cervical cancer. Mater. Sci. Eng. C Acknowledgements
94, 291–302 (2019). M.J.M. acknowledges support from a US National Institutes of Health (NIH) Director’s New
176. Wei, L., Chen, J., Zhao, S., Ding, J. & Chen, X. Thermo-sensitive polypeptide hydrogel for Innovator Award (DP2 TR002776), a Burroughs Wellcome Fund Career Award at the Scientific
locally sequential delivery of two-pronged antitumor drugs. Acta Biomater. 58, 44–53 Interface (CASI), a US National Science Foundation CAREER Award (CBET-2145491), an
(2017). American Cancer Society Research Scholar Grant (RSG-22-122-01-ET), and the National
177. Xiao, C. et al. Biomimetic nanoparticles loading with gamabutolin-indomethacin for Institutes of Health (NCI R01 CA241661, NCI R37 CA244911 and NIDDK R01 DK123049).
chemo/photothermal therapy of cervical cancer and anti-inflammation. J. Control. Rel. K.L.S. acknowledges support from the US National Science Foundation Graduate Research
339, 259–273 (2021). Fellowship.
178. Zhao, Z., Zhang, X., Li, C. & Chen, T. Designing luminescent ruthenium prodrug
for precise cancer therapy and rapid clinical diagnosis. Biomaterials 192, 579–589
Author contributions
(2019).
K.L.S. contributed to conceptualization, writing the original draft, reviewing and editing the
179. Wang, L. & Jia, E. Ovarian cancer targeted hyaluronic acid-based nanoparticle system
text. A.S.R. and W.H.P. contributed to writing, reviewing and editing. M.J.M. contributed to
for paclitaxel delivery to overcome drug resistance. Drug Deliv. 23, 1810–1817 (2016).
conceptualization, writing, reviewing and editing, and was responsible for supervision and
180. Ma, X. et al. Gold nanoparticles cause size-dependent inhibition of embryonic development
funding acquisition.
during murine pregnancy. Nano Res. https://doi.org/10.1007/s12274-018-1969-0 (2018).
181. Bolandparvaz, A. et al. Biodistribution and toxicity of epitope-functionalized dextran
iron oxide nanoparticles in a pregnant murine model. J. Biomed. Mater. Res. Part A 108, Competing interests
1186–1202 (2020). The authors declare no competing interests.
182. Tang, H. et al. Uptake and transport of pullulan acetate nanoparticles in the BeWo b30
placental barrier cell model. Int. J. Nanomed. 13, 4073–4082 (2018). Additional information
183. Sezgin-Bayindir, Z., Elcin, A. E., Parmaksiz, M., Elcin, Y. M. & Yuksel, N. Investigations on Peer review information Nature Reviews Bioengineering thanks Tina Buerki-Thurnherr, Thomas
clonazepam-loaded polymeric micelle-like nanoparticles for safe drug administration Rduch and the other, anonymous, reviewer(s) for their contribution to the peer review of this
during pregnancy. J. Microencapsul. 35, 149–164 (2018). work.
184. Turanov, A. A. et al. RNAi modulation of placental sFLT1 for the treatment of preeclampsia.
Nat. Biotechnol. https://doi.org/10.1038/nbt.4297 (2018). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
This article reports the development of cholesterol–siRNA conjugates for extrahepatic published maps and institutional affiliations.
gene silencing in the placenta in a baboon model of pre-eclampsia.
185. Colafella, K. M. M. & Denton, K. M. Sex-specific differences in hypertension and Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this
associated cardiovascular disease. Nat. Rev. Nephrol. 14, 185–201 (2018). article under a publishing agreement with the author(s) or other rightsholder(s); author self-
186. Gerdts, E. & Regitz-Zagrosek, V. Sex differences in cardiometabolic disorders. Nat. Med. archiving of the accepted manuscript version of this article is solely governed by the terms of
25, 1657–1666 (2019). such publishing agreement and applicable law.
187. Takahashi, T. et al. Sex differences in immune responses that underlie COVID-19 disease
outcomes. Nature 588, 315–320 (2020). © Springer Nature Limited 2023

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