Abstract
Nanoparticles exhibit distinctive physical and chemical properties that make them effective mediators for optical, magnetic or electric signal transduction. Consequently, nanoparticles are increasingly used in the development of biosensing systems that can detect diseases rapidly and accurately, with potential applications extending to point-of-care settings. In this Review, we discuss key aspects of translating nanoparticles into clinical diagnostics, including particle optimization, device construction and biosensing applications. We focus on two representative particle types; gold nanoparticles and magnetic ferrite nanoparticles, which are widely used in biosensing. We explain the characteristics of these particles and illustrate how they can be tailored to detect various analytical targets such as nucleic acids, proteins and small molecules. Finally, we discuss emerging research directions to advance the clinical integration of nanoparticle assays.
Key points
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Nanoparticles exhibit distinctive physical and chemical properties that make them effective mediators for optical, magnetic or electric signal transduction.
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Nanoparticles can be used for in vitro biosensing, targeting various analytes such as nucleic acids, proteins and small molecules.
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Gold nanoparticles and magnetic ferrite nanoparticles are the most widely used particles for biosensors to detect diseases rapidly and accurately.
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Physical properties of nanoparticles can be fine-tuned by adjusting their size, shape and composition to improve the sensitivity of analytical assays or to expand their applicability in point-of-care testing.
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To promote the translation of nanoparticle-based assays into clinical diagnostic tests, analytical accuracy, environmental safety and good manufacturing practices should be validated to ensure high performance standards.
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References
Borrebaeck, C. A. Precision diagnostics: moving towards protein biomarker signatures of clinical utility in cancer. Nat. Rev. Cancer 17, 199â204 (2017).
Vashist, S. K. In vitro diagnostic assays for COVID-19: recent advances and emerging trends. Diagnostics 10, 202 (2020).
Sun, X. M., Wan, J. J. & Qian, K. Designed microdevices for in vitro diagnostics. Small Methods 1, 1700196 (2017).
Liu, D. et al. Integrated microfluidic devices for in vitro diagnostics at point of care. Aggregate 3, e184 (2022).
Song, P. et al. Limitations and opportunities of technologies for the analysis of cell-free DNA in cancer diagnostics. Nat. Biomed. Eng. 6, 232â245 (2022).
Land, K. J., Boeras, D. I., Chen, X. S., Ramsay, A. R. & Peeling, R. W. REASSURED diagnostics to inform disease control strategies, strengthen health systems and improve patient outcomes. Nat. Microbiol. 4, 46â54 (2019).
Kairdolf, B. A., Qian, X. & Nie, S. Bioconjugated nanoparticles for biosensing, in vivo imaging, and medical diagnostics. Anal. Chem. 89, 1015â1031 (2017). This review presents bioconjugated NPs for biomolecular detection in clinically relevant applications.
Zhou, W., Gao, X., Liu, D. & Chen, X. Gold nanoparticles for in vitro diagnostics. Chem. Rev. 115, 10575â10636 (2015).
Tam, F., Goodrich, G. P., Johnson, B. R. & Halas, N. J. Plasmonic enhancement of molecular fluorescence. Nano Lett. 7, 496â501 (2007).
Yin, B. et al. Magnetic-responsive surface-enhanced Raman scattering platform with tunable hot spot for ultrasensitive virus nucleic acid detection. ACS Appl. Mater. Interfaces 14, 4714â4724 (2022).
Liu, Y. et al. fM-aM detection of the SARS-CoV-2 antigen by advanced lateral flow immunoassay based on gold nanospheres. ACS Appl. Nano. Mater. 4, 13826â13837 (2021).
Marquina, C. et al. GMR sensors and magnetic nanoparticles for immuno-chromatographic assays. J. Magn. Magn. Mater. 324, 3495â3498 (2012).
Nam, J. M., Thaxton, C. S. & Mirkin, C. A. Nanoparticle-based bio-bar codes for the ultrasensitive detection of proteins. Science 301, 1884â1886 (2003).
Blum, A. P. et al. Stimuli-responsive nanomaterials for biomedical applications. J. Am. Chem. Soc. 137, 2140â2154 (2015).
Chang, D., Ma, Y., Xu, X., Xie, J. & Ju, S. Stimuli-responsive polymeric nanoplatforms for cancer therapy. Front. Bioeng. Biotechnol. 9, 707319 (2021).
Paliwal, R., Babu, R. J. & Palakurthi, S. Nanomedicine scale-up technologies: feasibilities and challenges. AAPS PharmSciTech 15, 1527â1534 (2014).
Kwon, H. J. et al. Large-scale synthesis and medical applications of uniform-sized metal oxide nanoparticles. Adv. Mater. 30, e1704290 (2018).
Gupta, R. & Xie, H. Nanoparticles in daily life: applications, toxicity and regulations. J. Environ. Pathol. Toxicol. Oncol. 37, 209â230 (2018).
Fadeel, B. & Garcia-Bennett, A. E. Better safe than sorry: understanding the toxicological properties of inorganic nanoparticles manufactured for biomedical applications. Adv. Drug Deliv. Rev. 62, 362â374 (2010).
Lee, J. H. et al. Plasmonic photothermal gold bipyramid nanoreactors for ultrafast real-time bioassays. J. Am. Chem. Soc. 139, 8054â8057 (2017).
Suea-Ngam, A. et al. Enzyme-assisted nucleic acid detection for infectious disease diagnostics: moving toward the point-of-care. ACS Sens. 5, 2701â2723 (2020).
Szilagyi, M. et al. Circulating cell-free nucleic acids: main characteristics and clinical application. Int. J. Mol. Sci. 21, 6827 (2020).
Fouz, M. F. & Appella, D. H. PNA clamping in nucleic acid amplification protocols to detect single nucleotide mutations related to cancer. Molecules 25, 786 (2020).
Hermida-Romero, M. T. et al. Molecular detection of lymph node metastases in lung cancer patients using the one-step nucleic acid amplification method:clinical significance and prognostic value. Cells 11, 4010 (2022).
Sulleiro, E., Munoz-Calderon, A. & Schijman, A. G. Role of nucleic acid amplification assays in monitoring treatment response in chagas disease: usefulness in clinical trials. Acta Trop. 199, 105120 (2019).
Morgenstern, C., Cabric, S., Perka, C., Trampuz, A. & Renz, N. Synovial fluid multiplex PCR is superior to culture for detection of low-virulent pathogens causing periprosthetic joint infection. Diagn. Microbiol. Infect. Dis. 90, 115â119 (2018).
Cheong, J. et al. Fast detection of SARS-CoV-2 RNA via the integration of plasmonic thermocycling and fluorescence detection in a portable device. Nat. Biomed. Eng. 4, 1159â1167 (2020). This article presents a detection method for SARS-CoV-2 RNA by plasmonic thermocycling.
Hanash, S. M., Pitteri, S. J. & Faca, V. M. Mining the plasma proteome for cancer biomarkers. Nature 452, 571â579 (2008).
Blennow, K., Hampel, H., Weiner, M. & Zetterberg, H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat. Rev. Neurol. 6, 131â144 (2010).
Crick, F. H. On protein synthesis. Symp. Soc. Exp. Biol. 12, 138â163 (1958).
Gao, Y., Huang, X., Zhu, Y. & Lv, Z. A brief review of monoclonal antibody technology and its representative applications in immunoassays. J. Immunoass. Immunochem. 39, 351â364 (2018).
Brennan, D. J., OâConnor, D. P., Rexhepaj, E., Ponten, F. & Gallagher, W. M. Antibody-based proteomics: fast-tracking molecular diagnostics in oncology. Nat. Rev. Cancer 10, 605â617 (2010).
Suhre, K. et al. Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping. Nat. Commun. 15, 989 (2024).
Dalirirad, S., Han, D. & Steckl, A. J. Aptamer-based lateral flow biosensor for rapid detection of salivary cortisol. ACS Omega 5, 32890â32898 (2020).
Griss, R. et al. Bioluminescent sensor proteins for point-of-care therapeutic drug monitoring. Nat. Chem. Biol. 10, 598â603 (2014).
Zhao, S. S. et al. Miniature multi-channel SPR instrument for methotrexate monitoring in clinical samples. Biosens. Bioelectron. 64, 664â670 (2015).
Wu, Y. Y., Huang, P. & Wu, F. Y. A label-free colorimetric aptasensor based on controllable aggregation of AuNPs for the detection of multiplex antibiotics. Food Chem. 304, 125377 (2020).
Ruscito, A. & DeRosa, M. C. Small-molecule binding aptamers: selection strategies, characterization, and applications. Front. Chem. 4, 14 (2016).
Peltomaa, R., Glahn-Martinez, B., Benito-Pena, E. & Moreno-Bondi, M. C. Optical biosensors for label-free detection of small molecules. Sensors 18, 4126 (2018).
Wang, X., Cohen, L., Wang, J. & Walt, D. R. Competitive immunoassays for the detection of small molecules using single molecule arrays. J. Am. Chem. Soc. 140, 18132â18139 (2018).
Xu, J. X., Alom, M. S., Yadav, R. & Fitzkee, N. C. Predicting protein function and orientation on a gold nanoparticle surface using a residue-based affinity scale. Nat. Commun. 13, 7313 (2022).
Ma, F., Li, C. C. & Zhang, C. Y. Development of quantum dot-based biosensors: principles and applications. J. Mater. Chem. B 6, 6173â6190 (2018).
Huang, C. H. et al. Compact and filter-free luminescence biosensor for mobile in vitro diagnoses. ACS Nano 13, 11698â11706 (2019).
Ji, C., Zhou, Y., Leblanc, R. M. & Peng, Z. Recent developments of carbon dots in biosensing: a review. ACS Sens. 5, 2724â2741 (2020).
Afreen, S., He, Z., Xiao, Y. & Zhu, J. J. Nanoscale metal-organic frameworks in detecting cancer biomarkers. J. Mater. Chem. B 8, 1338â1349 (2020).
Nikolova, M. P., Joshi, P. B. & Chavali, M. S. Updates on biogenic metallic and metal oxide nanoparticles: therapy, drug delivery and cytotoxicity. Pharmaceutics 15, 1650 (2023).
Yang, S. Z. et al. Recent progress in the optical detection of pathogenic bacteria based on noble metal nanoparticles. Mikrochim. Acta. 188, 258 (2021).
Wang, L., Kafshgari, M. H. & Meunier, M. Optical properties and applications of plasmonic-metal nanoparticles. Adv. Funct. Mater. 30, 2005400 (2020).
Nilghaz, A. et al. Noble-metal nanoparticle-based colorimetric diagnostic assays for point-of-need applications. ACS Appl. Nano. Mater. 4, 12808â12824 (2021).
Eivazzadeh-Keihan, R. et al. Functionalized magnetic nanoparticles for the separation and purification of proteins and peptides. TrAC Trends Anal. Chem. 141, 116291 (2021).
Poudineh, M. et al. Tracking the dynamics of circulating tumour cell phenotypes using nanoparticle-mediated magnetic ranking. Nat. Nanotechnol. 12, 274â281 (2017).
Wuithschick, M. et al. Turkevich in new robes: key questions answered for the most common gold nanoparticle synthesis. ACS Nano 9, 7052â7071 (2015).
Yeh, Y. C., Creran, B. & Rotello, V. M. Gold nanoparticles: preparation, properties, and applications in bionanotechnology. Nanoscale 4, 1871â1880 (2012). This review discusses multiple attributes of AuNPs and their potential use in sensing, imaging and therapeutics.
Agunloye, E., Panariello, L., Gavriilidis, A. & Mazzei, L. A model for the formation of gold nanoparticles in the citrate synthesis method. Chem. Eng. Sci. 191, 318â331 (2018).
Kelly, K. L., Coronado, E., Zhao, L. L. & Schatz, G. C. The optical properties of metal nanoparticles: the influence of size, shape, and dielectric environment. J. Phys. Chem. B 107, 668â677 (2003).
Fan, X. F., Zheng, W. T. & Singh, D. J. Light scattering and surface plasmons on small spherical particles. Light Sci. Appl. 3, e179 (2014).
Hong, Y. A. & Ha, J. W. Enhanced refractive index sensitivity of localized surface plasmon resonance inflection points in single hollow gold nanospheres with inner cavity. Sci. Rep. 12, 6983 (2022).
Jain, P. K., Lee, K. S., El-Sayed, I. H. & El-Sayed, M. A. Calculated absorption and scattering properties of gold nanoparticles of different size, shape, and composition: applications in biological imaging and biomedicine. J. Phys. Chem. B 110, 7238â7248 (2006).
Kusuma, S. A. F., Harmonis, J. A., Pratiwi, R. & Hasanah, A. N. Gold nanoparticle-based colorimetric sensors: properties and application in detection of heavy metals and biological molecules. Sensors 23, 8172 (2023).
Wang, B. et al. Smartphone-based platforms implementing microfluidic detection with image-based artificial intelligence. Nat. Commun. 14, 1341 (2023).
Parolo, C. et al. Tutorial: design and fabrication of nanoparticle-based lateral-flow immunoassays. Nat. Protoc. 15, 3788â3816 (2020).
Kaiser, L., Weisser, J., Kohl, M. & Deigner, H. P. Small molecule detection with aptamer based lateral flow assays: applying aptamer-C-reactive protein cross-recognition for ampicillin detection. Sci. Rep. 8, 5628 (2018).
Liang, T. et al. Investigation of reagent delivery formats in a multivalent malaria sandwich immunoassay and implications for assay performance. Anal. Chem. 88, 2311â2320 (2016).
Liang, P. et al. Ag nanoparticles with ultrathin au shell-based lateral flow immunoassay for colorimetric and SERS dual-mode detection of SARS-CoV-2 IgG. Anal. Chem. 94, 8466â8473 (2022).
Tan, C. W. et al. Use of a point-of-care test to rapidly assess levels of SARS-CoV-2 nasal neutralising antibodies in vaccinees and breakthrough infected individuals. Sci. Rep. 13, 20263 (2023).
Oeschger, T., Kret, L. & Erickson, D. Lateral flow assay for detection and recovery of live cell Neisseria gonorrhoeae. Curr. Res. Biotechnol. 4, 359â364 (2022).
Liu, G. et al. Aptamer-nanoparticle strip biosensor for sensitive detection of cancer cells. Anal. Chem. 81, 10013â10018 (2009).
Naorungroj, S., Teengam, P., Vilaivan, T. & Chailapakul, O. Paper-based DNA sensor enabling colorimetric assay integrated with smartphone for human papillomavirus detection. N. J. Chem 45, 6960â6967 (2021).
Reineck, P. et al. Distance and wavelength dependent quenching of molecular fluorescence by Au@SiO2 core-shell nanoparticles. ACS Nano 7, 6636â6648 (2013).
Anger, P., Bharadwaj, P. & Novotny, L. Enhancement and quenching of single-molecule fluorescence. Phys. Rev. Lett. 96, 113002 (2006).
Swierczewska, M., Lee, S. & Chen, X. The design and application of fluorophore-gold nanoparticle activatable probes. Phys. Chem. Chem. Phys. 13, 9929â9941 (2011).
Dubertret, B., Calame, M. & Libchaber, A. J. Single-mismatch detection using gold-quenched fluorescent oligonucleotides. Nat. Biotechnol. 19, 365â370 (2001).
Moskovits, M. Surface-enhanced spectroscopy. Rev. Mod. Phys. 57, 783â826 (1985).
Jia, J. et al. Spike growth on patterned gold nanoparticle scaffolds. Nano Lett. 23, 11260â11265 (2023).
Mayer, K. M. & Hafner, J. H. Localized surface plasmon resonance sensors. Chem. Rev. 111, 3828â3857 (2011).
Cardoso, V. F. et al. Advances in magnetic nanoparticles for biomedical applications. Adv. Healthc. Mater. 7, 1700845 (2018). This review provides an outlook of MNPs for advanced biomedical applications.
Coricovac, D. E. et al. Biocompatible colloidal suspensions based on magnetic iron oxide nanoparticles: synthesis, characterization and toxicological profile. Front. Pharmacol. 8, 154 (2017).
Valdiglesias, V. et al. Are iron oxide nanoparticles safe? Current knowledge and future perspectives. J. Trace Elem. Med. Biol. 38, 53â63 (2016).
Lee, H., Shin, T. H., Cheon, J. & Weissleder, R. Recent developments in magnetic diagnostic systems. Chem. Rev. 115, 10690â10724 (2015).
Patsula, V. et al. Superparamagnetic Fe3O4 nanoparticles: synthesis by thermal decomposition of iron(III) glucuronate and application in magnetic resonance imaging. ACS Appl. Mater. Interfaces 8, 7238â7247 (2016).
Lee, J. H. et al. Artificially engineered magnetic nanoparticles for ultra-sensitive molecular imaging. Nat. Med. 13, 95â99 (2007).
Jang, J. T. et al. Critical enhancements of MRI contrast and hyperthermic effects by dopant-controlled magnetic nanoparticles. Angew. Chem. Int. Ed. Engl. 48, 1234â1238 (2009).
Noh, S. H. et al. Nanoscale magnetism control via surface and exchange anisotropy for optimized ferrimagnetic hysteresis. Nano Lett. 12, 3716â3721 (2012).
Lu, L. T. et al. Synthesis of magnetic cobalt ferrite nanoparticles with controlled morphology, monodispersity and composition: the influence of solvent, surfactant, reductant and synthetic conditions. Nanoscale 7, 19596â19610 (2015).
Gutierrez, L. et al. Aggregation effects on the magnetic properties of iron oxide colloids. Nanotechnology 30, 112001 (2019).
Standley, K. J. Oxide Magnetic Materials 2nd edn (Clarendon Press, 1972).
Wang, Z. et al. Nanoparticle amplification labeling for high-performance magnetic cell sorting. Nano Lett. 22, 4774â4783 (2022).
Chhowalla, M. et al. The chemistry of two-dimensional layered transition metal dichalcogenide nanosheets. Nat. Chem. 5, 263â275 (2013).
Mia, A. K., Meyyappan, M. & Giri, P. K. Two-dimensional transition metal dichalcogenide based biosensors: from fundamentals to healthcare applications. Biosensors 13, 169 (2023).
Park, H. et al. Ultrasensitive and selective field-effect transistor-based biosensor created by rings of MoS2 nanopores. ACS Nano 16, 1826â1835 (2022).
Nam, H. et al. Multiple MoS2 transistors for sensing molecule interaction kinetics. Sci. Rep. 5, 10546 (2015).
Wasfi, A. et al. Real-time COVID-19 detection via graphite oxide-based field-effect transistor biosensors decorated with Pt/Pd nanoparticles. Sci. Rep. 12, 18155 (2022).
Guerrini, L., Alvarez-Puebla, R. A. & Pazos-Perez, N. Surface modifications of nanoparticles for stability in biological fluids. Materials 11, 1154 (2018). This review explains multiple surface modification methodologies to preserve the integrity and stability of NPs in biological fluids.
Bagwe, R. P., Hilliard, L. R. & Tan, W. Surface modification of silica nanoparticles to reduce aggregation and nonspecific binding. Langmuir 22, 4357â4362 (2006).
Bantz, C. et al. The surface properties of nanoparticles determine the agglomeration state and the size of the particles under physiological conditions. Beilstein J. Nanotechnol. 5, 1774â1786 (2014).
Studart, A. R., Amstad, E. & Gauckler, L. J. Colloidal stabilization of nanoparticles in concentrated suspensions. Langmuir 23, 1081â1090 (2007).
Bhattacharjee, K. & Prasad, B. L. V. Surface functionalization of inorganic nanoparticles with ligands: a necessary step for their utility. Chem. Soc. Rev. 52, 2573â2595 (2023).
Debayle, M. et al. Zwitterionic polymer ligands: an ideal surface coating to totally suppress protein-nanoparticle corona formation? Biomaterials 219, 119357 (2019).
Wang, Z. et al. Antifouling hydrogel-coated magnetic nanoparticles for selective isolation and recovery of circulating tumor cells. J. Mater. Chem. B 9, 677â682 (2021).
Liu, J., Dai, C. & Hu, Y. Aqueous aggregation behavior of citric acid coated magnetite nanoparticles: effects of pH, cations, anions, and humic acid. Environ. Res. 161, 49â60 (2018).
Zhu, N. et al. Surface modification of magnetic iron oxide nanoparticles. Nanomaterials 8, 810 (2018).
Sun, J., Guo, L., Bao, Y. & Xie, J. A simple, label-free AuNPs-based colorimetric ultrasensitive detection of nerve agents and highly toxic organophosphate pesticide. Biosens. Bioelectron. 28, 152â157 (2011).
Yuan, Y. et al. Effect of surface modification on magnetization of iron oxide nanoparticle colloids. Langmuir 28, 13051â13059 (2012).
Frank, L. A. et al. Chitosan as a coating material for nanoparticles intended for biomedical applications. React. Funct. Polym. 147, 104459 (2020).
Suk, J. S., Xu, Q., Kim, N., Hanes, J. & Ensign, L. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99, 28â51 (2016).
Robinson, D. B. et al. DNA-functionalized MFe2O4 (M = Fe, Co, or Mn) nanoparticles and their hybridization to DNA-functionalized surfaces. Langmuir 21, 3096â3103 (2005).
Wang, G. S., Ma, Y. Y., Tong, Y. & Dong, X. F. Synthesis, characterization and magnetorheological study of 3-aminopropyltriethoxysilane-modified Fe3O4 nanoparticles. Smart Mater. Struct. 25, 035028 (2016).
Skora, B., Szychowski, K. A. & Gminski, J. A concise review of metallic nanoparticles encapsulation methods and their potential use in anticancer therapy and medicine. Eur. J. Pharm. Biopharm. 154, 153â165 (2020).
Nam, J. et al. Surface engineering of inorganic nanoparticles for imaging and therapy. Adv. Drug Deliv. Rev. 65, 622â648 (2013).
Weissleder, R., Kelly, K., Sun, E. Y., Shtatland, T. & Josephson, L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat. Biotechnol. 23, 1418â1423 (2005).
Vaughan, H. J., Green, J. J. & Tzeng, S. Y. Cancer-targeting nanoparticles for combinatorial nucleic acid delivery. Adv. Mater. 32, e1901081 (2020).
Schreiber, C. L. & Smith, B. D. Molecular conjugation using non-covalent click chemistry. Nat. Rev. Chem. 3, 393â400 (2019).
Idiago-Lopez, J., Moreno-Antolin, E., de la Fuente, J. M. & Fratila, R. M. Nanoparticles and bioorthogonal chemistry joining forces for improved biomedical applications. Nanoscale Adv. 3, 1261â1292 (2021).
Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. Engl. 40, 2004â2021 (2001).
Colombo, M. et al. Site-specific conjugation of ScFvs antibodies to nanoparticles by bioorthogonal strain-promoted alkyne-nitrone cycloaddition. Angew. Chem. Int. Ed. Engl. 51, 496â499 (2012).
Liu, R. et al. Click-functionalized SERS nanoprobes with improved labeling efficiency and capability for cancer cell imaging. ACS Appl. Mater. Interfaces 9, 38222â38229 (2017).
Algar, W. R. et al. The controlled display of biomolecules on nanoparticles: a challenge suited to bioorthogonal chemistry. Bioconjug. Chem. 22, 825â858 (2011).
Di Marco, M. et al. Overview of the main methods used to combine proteins with nanosystems: absorption, bioconjugation, and encapsulation. Int. J. Nanomed. 5, 37â49 (2010).
Dennler, P., Fischer, E. & Schibli, R. Antibody conjugates: from heterogeneous populations to defined reagents. Antibodies 4, 197â224 (2015).
Hoose, A., Vellacott, R., Storch, M., Freemont, P. S. & Ryadnov, M. G. DNA synthesis technologies to close the gene writing gap. Nat. Rev. Chem. 7, 144â161 (2023).
Poonthiyil, V., Lindhorst, T. K., Golovko, V. B. & Fairbanks, A. J. Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles. Beilstein J. Org. Chem. 14, 11â24 (2018).
Leriche, G., Chisholm, L. & Wagner, A. Cleavable linkers in chemical biology. Bioorg. Med. Chem. 20, 571â582 (2012).
Witt, D. Recent developments in disulfide bond formation. Synthesis 16, 2491â2509 (2008).
Beard, H. A., Korovesis, D., Chen, S. & Verhelst, S. H. L. Cleavable linkers and their application in MS-based target identification. Mol. Omics 17, 197â209 (2021).
Sun, N. et al. Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring. Nat. Commun. 11, 4489 (2020).
Flynn, C. D. et al. Biomolecular sensors for advanced physiological monitoring. Nat. Rev. Bioeng. 1, 560â575 (2023).
Lee, C. Y. et al. Development of integrated systems for on-site infection detection. Acc. Chem. Res. 54, 3991â4000 (2021).
Altug, H., Oh, S. H., Maier, S. A. & Homola, J. Advances and applications of nanophotonic biosensors. Nat. Nanotechnol. 17, 5â16 (2022).
Farka, Z., Jurik, T., Kovar, D., Trnkova, L. & Skladal, P. Nanoparticle-based immunochemical biosensors and assays: recent advances and challenges. Chem. Rev. 117, 9973â10042 (2017).
Malik, S. et al. Nanomaterials-based biosensor and their applications: a review. Heliyon 9, e19929 (2023).
Ji, D., Zhao, J., Liu, Y. & Wei, D. Electrical nanobiosensors for nucleic acid based diagnostics. J. Phys. Chem. Lett. 14, 4084â4095 (2023).
Melnychuk, N. & Klymchenko, A. S. DNA-functionalized dye-loaded polymeric nanoparticles: ultrabright FRET platform for amplified detection of nucleic acids. J. Am. Chem. Soc. 140, 10856â10865 (2018).
Moabelo, K. L. et al. Nanotechnology-based strategies for effective and rapid detection of SARS-CoV-2. Materials 14, 7851 (2021).
Blumenfeld, N. R. et al. Multiplexed reverse-transcriptase quantitative polymerase chain reaction using plasmonic nanoparticles for point-of-care COVID-19 diagnosis. Nat. Nanotechnol. 17, 984â992 (2022).
Qiu, G. et al. Dual-functional plasmonic photothermal biosensors for highly accurate severe acute respiratory syndrome coronavirus 2 detection. ACS Nano 14, 5268â5277 (2020). This article reports SARS-CoV-2 detection through localized surface plasmonic resonance sensing, exploiting the photothermal effect of plasmonic NPs.
Tang, C. et al. Application of magnetic nanoparticles in nucleic acid detection. J. Nanobiotechnol. 18, 62 (2020).
Chung, H. J., Castro, C. M., Im, H., Lee, H. & Weissleder, R. A magneto-DNA nanoparticle system for rapid detection and phenotyping of bacteria. Nat. Nanotechnol 8, 369â375 (2013). This article presents a dual-probe NP system for detecting and phenotyping human pathogens by microNMR by detecting targets labelled with MNPs.
Vrettou, C. S. et al. Accuracy of T2 magnetic resonance assays as point-of-care methods in the intensive care unit. J. Hosp. Infect. 139, 240â248 (2023).
You, M. et al. Ultrafast photonic PCR based on photothermal nanomaterials. Trends. Biotechnol. 38, 637â649 (2020).
Morozov, V. N., Kolyvanova, M. A., Dementâeva, O. V., Rudoy, V. M. & Kuzmin, V. A. Fluorescence superquenching of SYBR Green I in crowded DNA by gold nanoparticles. J. Lumin. 219, 116898 (2020).
Gao, L., Yang, Q., Wu, P. & Li, F. Recent advances in nanomaterial-enhanced enzyme-linked immunosorbent assays. Analyst 145, 4069â4078 (2020).
Billingsley, M. M., Riley, R. S. & Day, E. S. Antibody-nanoparticle conjugates to enhance the sensitivity of ELISA-based detection methods. PLoS One 12, e0177592 (2017).
Satija, J., Punjabi, N., Mishra, D. & Mukherji, S. Plasmonic-ELISA: expanding horizons. RSC Adv. 6, 85440â85456 (2016).
Thanh, N. T. K. & Rosenzweig, Z. Development of an aggregation-based immunoassay for anti-protein A using gold nanoparticles. Anal. Chem. 74, 1624â1628 (2002).
Wu, J. et al. Nanomaterials with enzyme-like characteristics (nanozymes): next-generation artificial enzymes (II). Chem. Soc. Rev. 48, 1004â1076 (2019).
Das, B. et al. Nanozymes in point-of-care diagnosis: an emerging futuristic approach for biosensing. Nano-Micro Lett. 13, 193 (2021).
Mirica, A. C. et al. Latest trends in lateral flow immunoassay (LFIA) detection labels and conjugation process. Front. Bioeng. Biotechnol. 10, 922772 (2022).
Alkilany, A. M. et al. Colloidal stability of citrate and mercaptoacetic acid capped gold nanoparticles upon lyophilization: effect of capping ligand attachment and type of cryoprotectants. Langmuir 30, 13799â13808 (2014).
Hamaly, M. A., Abulateefeh, S. R., Al-Qaoud, K. M. & Alkilany, A. M. Freeze-drying of monoclonal antibody-conjugated gold nanorods: colloidal stability and biological activity. Int. J. Pharm. 550, 269â277 (2018).
Posthuma-Trumpie, G. A., Korf, J. & van Amerongen, A. Lateral flow (immuno)assay: its strengths, weaknesses, opportunities and threats. A literature survey. Anal. Bioanal. Chem. 393, 569â582 (2009). This review discusses strengths, weaknesses, opportunities and challenges of NP-based lateral flow immunoassays.
Sloan-Dennison, S., OâConnor, E., Dear, J. W., Graham, D. & Faulds, K. Towards quantitative point of care detection using SERS lateral flow immunoassays. Anal. Bioanal. Chem. 414, 4541â4549 (2022).
Liu, Y., Zhan, L., Qin, Z., Sackrison, J. & Bischof, J. C. Ultrasensitive and highly specific lateral flow assays for point-of-care diagnosis. ACS Nano 15, 3593â3611 (2021).
Gupta, R. et al. Ultrasensitive lateral-flow assays via plasmonically active antibody-conjugated fluorescent nanoparticles. Nat. Biomed. Eng. 7, 1556â1570 (2023).
Hwang, J., Lee, S. & Choo, J. Application of a SERS-based lateral flow immunoassay strip for the rapid and sensitive detection of staphylococcal enterotoxin B. Nanoscale 8, 11418â11425 (2016).
Li, W. et al. Battery-triggered ultrasensitive electrochemiluminescence detection on microfluidic paper-based immunodevice based on dual-signal amplification strategy. Anal. Chim. Acta 767, 66â74 (2013).
Taton, K., Johnson, D., Guire, P., Lange, E. & Tondra, M. Lateral flow immunoassay using magnetoresistive sensors. J. Magn. Magn. Mater. 321, 1679â1682 (2009).
Gong, Y. et al. A portable and universal upconversion nanoparticle-based lateral flow assay platform for point-of-care testing. Talanta 201, 126â133 (2019).
Chen, Z. et al. Rapid and sensitive detection of anti-SARS-CoV-2 IgG, using lanthanide-doped nanoparticles-based lateral flow immunoassay. Anal. Chem. 92, 7226â7231 (2020).
Mak, W. C., Beni, V. & Turner, A. P. F. Lateral-flow technology: from visual to instrumental. TrAC Trends Anal. Chem. 79, 297â305 (2016).
Tran, V., Walkenfort, B., Konig, M., Salehi, M. & Schlucker, S. Rapid, quantitative, and ultrasensitive point-of-care testing: a portable SERS reader for lateral flow assays in clinical chemistry. Angew. Chem. Int. Ed. Engl. 58, 442â446 (2019).
Rissin, D. M. et al. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat. Biotechnol. 28, 595â599 (2010).
Cohen, L. et al. Single molecule protein detection with attomolar sensitivity using droplet digital enzyme-linked immunosorbent assay. ACS Nano 14, 9491â9501 (2020).
Akama, K., Shirai, K. & Suzuki, S. Droplet-free digital enzyme-linked immunosorbent assay based on a tyramide signal amplification system. Anal. Chem. 88, 7123â7129 (2016).
Curtin, K., Fike, B. J., Binkley, B., Godary, T. & Li, P. Recent advances in digital biosensing technology. Biosensors 12, 673 (2022).
Monroe, M. R. et al. Single nanoparticle detection for multiplexed protein diagnostics with attomolar sensitivity in serum and unprocessed whole blood. Anal. Chem. 85, 3698â3706 (2013).
Li, J. R. et al. A digital single-molecule nanopillar SERS platform for predicting and monitoring immune toxicities in immunotherapy. Nat. Commun. 12, 1087 (2021).
Mahmoudi, M., Landry, M. P., Moore, A. & Coreas, R. The protein corona from nanomedicine to environmental science. Nat. Rev. Mater. 8, 422â438 (2023).
Monopoli, M. P., Aberg, C., Salvati, A. & Dawson, K. A. Biomolecular coronas provide the biological identity of nanosized materials. Nat. Nanotechnol. 7, 779â786 (2012).
Gardner, L., Kostarelo, K., Mallick, P., Dive, C. & Hadjidemetriou, M. Nano-omics: nanotechnology-based multidimensional harvesting of the blood-circulating cancerome. Nat. Rev. Clin. Oncol. 19, 551â561 (2022).
Blume, J. E. et al. Rapid, deep and precise profiling of the plasma proteome with multi-nanoparticle protein corona. Nat. Commun. 11, 3662 (2020).
Grys, D. B. et al. Controlling atomic-scale restructuring and cleaning of gold nanogap multilayers for surface-enhanced Raman scattering sensing. ACS Sens. 8, 2879â2888 (2023).
Sibug-Torres, S. M. et al. In situ electrochemical regeneration of nanogap hotspots for continuously reusable ultrathin SERS sensors. Nat. Commun. 15, 2022 (2024).
Plou, J. et al. Prospects of surface-enhanced Raman spectroscopy for biomarker monitoring toward precision medicine. ACS Photonics 9, 333â350 (2022).
Lee, W. et al. Spread spectrum SERS allows label-free detection of attomolar neurotransmitters. Nat. Commun. 12, 159 (2021).
Cho, H. et al. Surface-enhanced Raman spectroscopy-based label-free insulin detection at physiological concentrations for analysis of islet performance. ACS Sens. 3, 65â71 (2018).
Shalabaeva, V. et al. Time resolved and label free monitoring of extracellular metabolites by surface enhanced Raman spectroscopy. PLoS One 12, e0175581 (2017).
Liana, D. D., Raguse, B., Gooding, J. J. & Chow, E. Recent advances in paper-based sensors. Sensors 12, 11505â11526 (2012).
Xu, K., Zhou, R., Takei, K. & Hong, M. Toward flexible surface-enhanced Raman scattering (SERS) sensors for point-of-care diagnostics. Adv. Sci. 6, 1900925 (2019).
Li, Y. et al. A three-dimensional silver nanoparticles decorated plasmonic paper strip for SERS detection of low-abundance molecules. Talanta 147, 493â500 (2016).
Yu, W. W. & White, I. M. Inkjet printed surface enhanced Raman spectroscopy array on cellulose paper. Anal. Chem. 82, 9626â9630 (2010).
Romo-Herrera, J. M. et al. Paper-based plasmonic substrates as surface-enhanced Raman scattering spectroscopy platforms for cell culture applications. Mater. Today Bio. 11, 100125 (2021).
Cheng, H. et al. Drug preconcentration and direct quantification in biofluids using 3D-Printed paper cartridge. Biosens. Bioelectron. 189, 113266 (2021).
Restaino, S. M., Berger, A. & White, I. M. Inkjet-printed paper fluidic devices for onsite detection of antibiotics using surface-enhanced Raman spectroscopy. Methods Mol. Biol. 1572, 525â540 (2017).
Berger, A. G., Restaino, S. M. & White, I. M. Vertical-flow paper SERS system for therapeutic drug monitoring of flucytosine in serum. Anal. Chim. Acta 949, 59â66 (2017).
Ates, H. C. et al. On-site therapeutic drug monitoring. Trends Biotechnol. 38, 1262â1277 (2020).
Lin, H. Y. et al. Direct thermal growth of gold nanopearls on 3D interweaved hydrophobic fibers as ultrasensitive portable SERS substrates for clinical applications. Small 19, e2207404 (2023).
Ahmed, S. et al. Current advances in immunoassays for the detection of antibiotics residues: a review. Food Agr. Immunol. 31, 268â290 (2020).
Xiong, Y., Leng, Y. K., Li, X. M., Huang, X. L. & Xiong, Y. H. Emerging strategies to enhance the sensitivity of competitive ELISA for detection of chemical contaminants in food samples. TrAC Trends Anal. Chem. 126, 115861 (2020).
Hulme, E. C. & Trevethick, M. A. Ligand binding assays at equilibrium: validation and interpretation. Br. J. Pharmacol. 161, 1219â1237 (2010).
Li, D. et al. Ultrasensitive competitive lateral flow immunoassay with visual semiquantitative inspection and flexible quantification capabilities. Anal. Chem. 94, 2996â3004 (2022).
Apilux, A., Rengpipat, S., Suwanjang, W. & Chailapakul, O. Development of competitive lateral flow immunoassay coupled with silver enhancement for simple and sensitive salivary cortisol detection. EXCLI J. 17, 1198â1209 (2018).
Sotnikov, D. V., Barshevskaya, L. V., Bartosh, A. V., Zherdev, A. V. & Dzantiev, B. B. Double competitive immunodetection of small analyte: realization for highly sensitive lateral flow immunoassay of chloramphenicol. Biosensors 12, 343 (2022).
Yu, H. et al. A rapid assay provides on-site quantification of tetrahydrocannabinol in oral fluid. Sci. Transl. Med. 13, eabe2352 (2021).
Di Nardo, F., Chiarello, M., Cavalera, S., Baggiani, C. & Anfossi, L. Ten years of lateral flow immunoassay technique applications: trends, challenges and future perspectives. Sensors 21, 5185 (2021).
Ardalan, S. & Ignaszak, A. Innovations and challenges in electroanalytical tools for rapid biosurveillance of SARS-CoV-2. Adv. Mater. Technol. 7, 2200208 (2022).
Zhao, H. et al. Ultrasensitive supersandwich-type electrochemical sensor for SARS-CoV-2 from the infected COVID-19 patients using a smartphone. Sens. Actuators B Chem. 327, 128899 (2021).
Hwang, H. et al. MESIA: magnetic force-assisted electrochemical sandwich immunoassays for quantification of prostate-specific antigen in human serum. Anal. Chim. Acta. 1061, 92â100 (2019).
Khalid, M. F. et al. Performance of rapid antigen tests for COVID-19 diagnosis: a systematic review and meta-analysis. Diagnostics 12, 110 (2022).
Green, D. A. & StGeorge, K. Rapid antigen tests for influenza: rationale and significance of the FDA reclassification. J. Clin. Microbiol. 56, e00711-18 (2018).
Wahl, C. B. et al. Machine learning-accelerated design and synthesis of polyelemental heterostructures. Sci. Adv. 7, eabj5505 (2021).
Raccuglia, P. et al. Machine-learning-assisted materials discovery using failed experiments. Nature 533, 73â76 (2016).
Wiggins, W. F. & Tejani, A. S. On the opportunities and risks of foundation models for natural language processing in radiology. Radiol. Artif. Intell. 4, e220119 (2022).
Bradbury, A. & Pluckthun, A. Reproducibility: standardize antibodies used in research. Nature 518, 27â29 (2015).
Kricka, L. J. Human anti-animal antibody interferences in immunological assays. Clin. Chem. 45, 942â956 (1999).
Silva, D. A. et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature 565, 186â191 (2019).
Baek, M. & Baker, D. Deep learning and protein structure modeling. Nat. Methods 19, 13â14 (2022).
BelBruno, J. J. Molecularly imprinted polymers. Chem. Rev. 119, 94â119 (2019).
Jain, M., Olsen, H. E., Paten, B. & Akeson, M. The oxford nanopore MinION: delivery of nanopore sequencing to the genomics community. Genome Biol. 17, 239 (2016).
Naccache, S. N. et al. A cloud-compatible bioinformatics pipeline for ultrarapid pathogen identification from next-generation sequencing of clinical samples. Genome Res. 24, 1180â1192 (2014).
Abdolahpur Monikh, F. et al. Particle number-based trophic transfer of gold nanomaterials in an aquatic food chain. Nat. Commun. 12, 899 (2021).
Schmutz, M. et al. A methodological safe-by-design approach for the development of nanomedicines. Front. Bioeng. Biotechnol. 8, 258 (2020).
Burello, E. & Worth, A. P. QSAR modeling of nanomaterials. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 3, 298â306 (2011).
Fourches, D. et al. Quantitative nanostructure-activity relationship modeling. ACS Nano 4, 5703â5712 (2010).
Yang, Z. et al. Application of nanomaterials to enhance polymerase chain reaction. Molecules 27, 8854 (2022).
Teawprasong, P. et al. Solvent-sensitive nanoparticle-enhanced PCR assay for the detection of enterotoxigenic Escherichia coli. Sci. Rep. 12, 20677 (2022).
Mettenbrink, E. M., Yang, W. & Wilhelm, S. Bioimaging with upconversion nanoparticles. Adv. Photonics Res. 3, 20220909 (2022).
Koroleva, E. A., Shabalkin, I. D. & Krivoshapkin, P. V. Monometallic and alloy nanoparticles: a review of biomedical applications. J. Mater. Chem. B 11, 3054â3070 (2023).
Roh, Y. H. et al. CRISPR-enhanced hydrogel microparticles for multiplexed detection of nucleic acids. Adv. Sci. 10, e2206872 (2023).
Klosz, K. Quality management for the processing of medical devices. GMS Krankenhhyg. Interdiszip. 3, Doc22 (2008).
Jarow, J. P. & Baxley, J. H. Medical devices: US medical device regulation. Urol. Oncol. 33, 128â132 (2015).
Moore, W. & Frye, S. Review of HIPAA, part 1: history, protected health information, and privacy and security rules. J. Nucl. Med. Technol. 47, 269â272 (2019).
Acknowledgements
J. Cheon is supported by the Institute for Basic Science IBS-R026-D1. H.L. is supported by National Institutes of Health U01CA284982 and Massachusetts General Hospital scholar fund. J.H.L. is supported by Yonsei University Research Fund (2021-22-0323). A.J. is supported by a National Research Foundation NRF-2022R1C1C2008563 grant funded by the Korean government.
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J. Cheon and H.L. initiated the Review. J. Cheong and A.J. conducted the literature search. All authors developed the outline and contributed to the writing, reviewing and editing of the manuscript.
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Cheong, J., Jo, A., Lee, J. et al. Engineered nanoparticles for clinical assays. Nat Rev Bioeng (2024). https://doi.org/10.1038/s44222-024-00208-y
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DOI: https://doi.org/10.1038/s44222-024-00208-y