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Functional proteins are the most versatile macromolecules. They can be obtained by extraction from natural sources or by genetic engineering technologies. The outstanding selectivity, specificity, binding activity, and biocompatibility endow engineered proteins with outstanding performance for disease therapy. Nevertheless, their stability is dramatically impaired in blood circulation, hindering clinical translations. Thus, many strategies have been developed to improve the stability, efficacy, bioavailability, and productivity of therapeutic proteins for clinical applications. In this review, we summarize the recent progress in the fabrication and application of therapeutic proteins. We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly. Furthermore, we highlight their diverse applications as growth factors, nanovaccines, antibody-based drugs, bioimaging molecules, and cytokine receptor antagonists. Finally, a summary and perspective for the future development of therapeutic proteins are presented.

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Engineered protein nanodrug as an emerging therapeutic tool

Show Author's information Yuanxin Li1,2Jing Sun3Jingjing Li1( )Kai Liu1,2,4( )Hongjie Zhang1,2,4
State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
University of Science and Technology of China, Hefei 230026, China
Institute of Organic Chemistry, University of Ulm, Albert-Einstein-Allee 11, Ulm 89081, Germany
Department of Chemistry, Tsinghua University, Beijing 100084, China


Functional proteins are the most versatile macromolecules. They can be obtained by extraction from natural sources or by genetic engineering technologies. The outstanding selectivity, specificity, binding activity, and biocompatibility endow engineered proteins with outstanding performance for disease therapy. Nevertheless, their stability is dramatically impaired in blood circulation, hindering clinical translations. Thus, many strategies have been developed to improve the stability, efficacy, bioavailability, and productivity of therapeutic proteins for clinical applications. In this review, we summarize the recent progress in the fabrication and application of therapeutic proteins. We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly. Furthermore, we highlight their diverse applications as growth factors, nanovaccines, antibody-based drugs, bioimaging molecules, and cytokine receptor antagonists. Finally, a summary and perspective for the future development of therapeutic proteins are presented.

Keywords: therapeutic proteins, nanodrug, genetic engineering, structural modification, therapeutic efficacy



Johnson-Léger, C.; Power, C. A.; Shomade, G.; Shaw, J. P.; Proudfoot, A. E. Protein therapeutics-lessons learned and a view of the future. Expert Opin. Biol. Ther. 2006, 6, 1–7.

Wen, F.; Rubin-Pitel, S. B.; Zhao, H. Engineering of therapeutic proteins. In Protein Engineering and Design. Park, S. J.; Cochran, J. R. Eds.; CRC Press: Boca Raton, 2009; pp 153–177.

Cheng, L.; Yang, L.; Meng, F. H.; Zhong, Z. Y. Protein nanotherapeutics as an emerging modality for cancer therapy. Adv. Healthc. Mater. 2018, 7, 1800685.


Usmani, S. S.; Bedi, G.; Samuel, J. S.; Singh, S.; Kalra, S.; Kumar, P.; Ahuja, A. A.; Sharma, M.; Gautam, A.; Raghava, G. P. S. THPdb: Database of FDA-approved peptide and protein therapeutics. PLoS One 2017, 12, e0181748.


Werle, M.; Bernkop-Schnürch, A. Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids 2006, 30, 351–367.


Zaman, R.; Islam, R. A.; Ibnat, N.; Othman, I.; Zaini, A.; Lee, C. Y.; Chowdhury, E. H. Current strategies in extending half-lives of therapeutic proteins. J. Control. Release 2019, 301, 176–189.


Bajracharya, R.; Song, J. G.; Back, S. Y.; Han, H. K. Recent advancements in non-invasive formulations for protein drug delivery. Comput. Struct. Biotechnol. J. 2019, 17, 1290–1308.


Wang, S. Y.; Duan, Y. O.; Zhang, Q. Z.; Komarla, A.; Gong, H.; Gao, W. W.; Zhang, L. F. Drug targeting via platelet membrane-coated nanoparticles. Small Struct. 2020, 1, 2000018.


Kozlowski, H. N.; Mohamed, M. A. A.; Kim, J.; Bell, N. G.; Zagorovsky, K.; Mubareka, S.; Chan, W. C. W. A Colorimetric test to differentiate patients infected with influenza from COVID-19. Small Struct. 2021, 2, 2100034.


Nguyen, V. H.; Lee, B. J. Protein corona: A new approach for nanomedicine design. Int. J. Nanomed. 2017, 12, 3137–3151.


Hong, S. Y. N.; Choi, D. W.; Kim, H. N.; Park, C. G.; Lee, W.; Park, H. H. Protein-based nanoparticles as drug delivery systems. Pharmaceutics 2020, 12, 604.


Zhang, N.; Mei, K.; Guan, P.; Hu, X.; Zhao, Y. L. Protein-based artificial nanosystems in cancer therapy. Small 2020, 16, 1907256.


Corchero, J. L.; Vázquez, E.; García-Fruitós, E.; Ferrer-Miralles, N.; Villaverde, A. Recombinant protein materials for bioengineering and nanomedicine. Nanomedicine (Lond) 2014, 9, 2817–2828.


Uzunalli, G.; Guler, M. O. Peptide gels for controlled release of proteins. Ther. Deliv. 2020, 11, 193–211.


Sandra, F.; Khaliq, N. U.; Sunna, A.; Care, A. Developing protein-based nanoparticles as versatile delivery systems for cancer therapy and imaging. Nanomaterials (Basel) 2019, 9, 1329.


Ferrer-Miralles, N.; Rodríguez-Carmona, E.; Corchero, J. L.; García-Fruitós, E.; Vázquez, E.; Villaverde, A. Engineering protein self-assembling in protein-based nanomedicines for drug delivery and gene therapy. Crit. Rev. Biotechnol. 2015, 35, 209–221.


Hassanin, I. A.; Elzoghby, A. O. Self-assembled non-covalent protein-drug nanoparticles: An emerging delivery platform for anti-cancer drugs. Expert Opin. Drug Deliv. 2020, 17, 1437–1458.


Yang, Y. Y.; Chen, Q. L.; Lin, J. Y.; Cai, Z.; Liao, G. C.; Wang, K.; Bai, L.; Zhao, P.; Yu, Z. Q. Recent advance in polymer based microspheric systems for controlled protein and peptide delivery. Curr. Med. Chem. 2019, 26, 2285–2296.


Patra, J. K.; Das, G.; Fraceto, L. F.; Campos, E. V. R.; Rodriguez-Torres, M. D. P.; Acosta-Torres, L. S.; Diaz-Torres, L. A.; Grillo, R.; Swamy, M. K.; Sharma, S. et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71.


Flintegaard, T. V.; Thygesen, P.; Rahbek-Nielsen, H.; Levery, S. B.; Kristensen, C.; Clausen, H.; Bolt, G. N-glycosylation increases the circulatory half-life of human growth hormone. Endocrinology 2010, 151, 5326–5336.


Strohl, W. R. Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs 2015, 29, 215–239.


Beals, J. M.; Shanafelt, A. B. Enhancing exposure of protein therapeutics. Drug Discov. Today Technol. 2006, 3, 87–94.


Ekladious, I.; Colson, Y. L.; Grinstaff, M. W. Polymer-drug conjugate therapeutics: Advances, insights and prospects. Nat. Rev. Drug Discov. 2019, 18, 273–294.


Feng, L. D.; Yang, L.; Li, L. J.; Xiao, J. Y.; Bie, N. N.; Xu, C.; Zhou, J.; Liu, H. M.; Gan, L.; Wu, Y. Z. Programmed albumin nanoparticles regulate immunosuppressive pivot to potentiate checkpoint blockade cancer immunotherapy. Nano Res. 2022, 15, 593–602.


Kontermann, R. E. Half-life extended biotherapeutics. Expert Opin. Biol. Ther. 2016, 16, 903–915.


Sleep, D. Albumin and its application in drug delivery. Expert Opin. Drug Deliv. 2015, 12, 793.


Cohen-Barak, O.; Sakov, A.; Rasamoelisolo, M.; Bassan, M.; Brown, K.; Mendzelevski, B.; Spiegelstein, O. Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency. Eur. J. Endocrinol. 2015, 173, 541–551.


Santagostino, E.; Martinowitz, U.; Lissitchkov, T.; Pan-Petesch, B.; Hanabusa, H.; Oldenburg, J.; Negrier, C.; Pabinger, I.; Prondzinski, M. V. D.; Altisent, C. et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: Results of a phase 3 trial. Blood 2016, 127, 1761–1769.


Shi, Y. N.; Sun, X. F.; Zhang, L. P.; Sun, K. X.; Li, K. K.; Li, Y. X.; Zhang, Q. Fc-modified exenatide-loaded nanoparticles for oral delivery to improve hypoglycemic effects in mice. Sci. Rep. 2018, 8, 726.


Jazayeri, J. A.; Carroll, G. J. Fc-based cytokines: Prospects for engineering superior therapeutics. BioDrugs 2008, 22, 11.


Pridgen, E. M.; Alexis, F.; Kuo, T. T.; Levy-Nissenbaum, E.; Karnik, R.; Blumberg, R. S.; Langer, R.; Farokhzad, O. C. Transepithelial transport of Fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci. Transl. Med. 2013, 5, 213ra167.


Liu, L. M. Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Prot. Cell 2018, 9, 15–32.


Nestorov, I.; Zitnik, R.; DeVries, T.; Nakanishi, A. M.; Wang, A.; Banfield, C. Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis. Br. J. Clin. Pharmacol. 2006, 62, 435–445.


Wells, J. A.; Glassman, A. R.; Ayala, A. R.; Jampol, L. M.; Bressler, N. M.; Bressler, S. B.; Brucker, A. J.; Ferris, F. L.; Hampton, G. R.; Jhaveri, C. et al. Aflibercept, Bevacizumab, or Ranibizumab for diabetic macular edema: Two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016, 123, 1351–1359.


Rath, T.; Baker, K.; Dumont, J. A.; Peters, R. T.; Jiang, H. Y.; Qiao, S. W.; Lencer, W. I.; Pierce, G. F.; Blumberg, R. S. Fc-fusion proteins and FcRn: Structural insights for longer-lasting and more effective therapeutics. Crit. Rev. Biotechnol. 2015, 35, 235–254.


Do, B. H.; Kang, H. J.; Song, J. A.; Nguyen, M. T.; Park, S.; Yoo, J.; Nguyen, A. N.; Kwon, G. G.; Jang, J.; Jang, M. et al. Granulocyte colony-stimulating factor (GCSF) fused with Fc domain produced from E. coli is less effective than Polyethylene Glycol-conjugated GCSF. Sci. Rep. 2017, 7, 6480.


Han, J. A.; Kang, Y. J.; Shin, C.; Ra, J. S.; Shin, H. H.; Hong, S. Y.;Do, Y.; Kang, S. Ferritin protein cage nanoparticles as versatile antigen delivery nanoplatforms for dendritic cell (DC)-based vaccine development. Nanomed. Nanotechnol. Biol. Med. 2014, 10, 561–569.


Deshpande, S.; Masurkar, N. D.; Girish, V. M.; Desai, M.; Chakraborty, G.; Chan, J. M.; Drum, C. L. Thermostable exoshells fold and stabilize recombinant proteins. Nat. Commun. 2017, 8, 1442.


Jeon, J. O.; Kim, S.; Choi, E.; Shin, K.; Cha, K.; So, I.; Kim, S. I.; Jun, E.; Kim, D. J.; Ahn, H. J. et al. Designed nanocage displaying ligand-specific peptide bunches for high affinity and biological activity. ACS Nano 2013, 7, 7462–7471.


Georgiev, I. S.; Joyce, M. G.; Chen, R. E.; Leung, K.; McKee, K.; Druz, A.; Van Galen, J. G.; Kanekiyo, M.; Tsybovsky, Y.; Yang, E. S. et al. Two-component ferritin nanoparticles for multimerization of diverse trimeric antigens. ACS Infect. Dis. 2018, 4, 788–796.


Almine, J. F.; Bax, D. V.; Mithieux, S. M.; Nivison-Smith, L.; Rnjak, J.; Waterhouse, A.; Wise, S. G.; Weiss, A. S. Elastin-based materials. Chem. Soc. Rev. 2010, 39, 3371–3379.


MacEwan, S. R.; Chilkoti, A. Elastin-like polypeptides: Biomedical applications of tunable biopolymers. Biopolymers 2010, 94, 60–77.


Koria, P.; Yagi, H.; Kitagawa, Y.; Megeed, Z.; Nahmias, Y.; Sheridan, R.; Yarmush, M. L. Self-assembling elastin-like peptides growth factor chimeric nanoparticles for the treatment of chronic wounds. Proc. Natl. Acad. Sci. USA 2011, 108, 1034–1039.


Wang, W.; Despanie, J.; Shi, P.; Edman, M. C.; Lin, Y. A.; Cui, H. G.; Heur, J. M.; Fini, M. E.; Hamm-Alvarez, S. F.; MacKay, J. A. Lacritin-mediated regeneration of the corneal epithelia by protein polymer nanoparticles. J. Mater. Chem. B 2014, 2, 8131–8141.


Caliceti, P.; Veronese, F. M. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv. Drug Deliv. Rev. 2003, 55, 1261–1277.


Qi, Y. Z.; Chilkoti, A. Protein-polymer conjugation-moving beyond PEGylation. Curr. Opin. Chem. Biol. 2015, 28, 181–193.


Steiert, E.; Radi, L.; Fach, M.; Wich, P. R. Protein-based nanoparticles for the delivery of enzymes with antibacterial activity. Macromol. Rapid Commun. 2018, 39, 1800186.


Grozdanovic, M.; Laffey, K. G.; Abdelkarim, H.; Hitchinson, B.; Harijith, A.; Moon, H. G.; Park, G. Y.; Rousslang, L. K.; Masterson, J. C.; Furuta, G. T. et al. Novel peptide nanoparticle-biased antagonist of CCR3 blocks eosinophil recruitment and airway hyperresponsiveness. J. Allergy Clin. Immunol. 2019, 143, 669–680.e12.


Li, J. J.; Li, B.; Sun, J.; Ma, C.; Wan, S. K.; Li, Y. X.; Göstl, R.; Herrmann, A.; Liu, K.; Zhang, H. J. Engineered near-infrared fluorescent protein assemblies for robust bioimaging and therapeutic applications. Adv. Mater. 2020, 32, 2000964.


Ma, C.; Li, B.; Zhang, J. R.; Sun, Y.; Li, J. J.; Zhou H. C.; Shen, J. L.; Gu, R.; Qian, J.; Fan, C. H. et al. Significantly improving the bioefficacy for rheumatoid arthritis with supramolecular nanoformulations. Adv. Mater. 2021, 33, 2100098.


Song, Q. X.; Song, H. H.; Xu, J. R.; Huang, J. L.; Hu, M.; Gu, X.; Chen, J.; Zheng, G.; Chen, H. Z.; Gao, X. L. Biomimetic ApoE-reconstituted high density lipoprotein nanocarrier for blood-brain barrier penetration and amyloid beta-targeting drug delivery. Mol. Pharm. 2016, 13, 3976–3987.


Song, Q. X.; Huang, M.; Yao, L.; Wang, X. L.; Gu, X.; Chen, J.; Chen, J.; Huang, J. L.; Hu, Q. Y.; Kang, T. et al. Lipoprotein-based nanoparticles rescue the memory loss of mice with Alzheimer’s disease by accelerating the clearance of amyloid-beta. ACS Nano 2014, 8, 2345.


Kim, S. K.; Foote, M. B.; Huang, L. The targeted intracellular delivery of cytochrome C protein to tumors using lipid-apolipoprotein nanoparticles. Biomaterials 2012, 33, 3959–3966.


Lee, H. J.; Park, H. H.; Kim, J. A.; Park, J. H.; Ryu, J.; Choi, J.; Lee, J.; Rhee, W. J.; Park, T. H. Enzyme delivery using the 30Kc19 protein and human serum albumin nanoparticles. Biomaterials 2014, 35, 1696–1704.


Jiang, Y. Y.; Lu, H. X.; Chen, F.; Callari, M.; Pourgholami, M.; Morris, D. L.; Stenzel, M. H. PEGylated albumin-based polyion complex micelles for protein delivery. Biomacromolecules 2016, 17, 808–817.


Pham, D. T.; Saelim, N.; Tiyaboonchai, W. Alpha mangostin loaded crosslinked silk fibroin-based nanoparticles for cancer chemotherapy. Colloids Surf. B Biointerf. 2019, 181, 705–713.


Pham, D. T.; Saelim, N.; Cornu, R.; Béduneau, A.; Tiyaboonchai, W. Crosslinked fibroin nanoparticles: Investigations on biostability, cytotoxicity, and cellular internalization. Pharmaceuticals (Basel) 2020, 13, 86.


Wang, S. H.; Xu, T.; Yang, Y. H.; Shao, Z. Z. Colloidal stability of silk fibroin nanoparticles coated with cationic polymer for effective drug delivery. ACS Appl. Mater. Interfaces 2015, 7, 21254–21262.


Kundu, J.; Chung, Y. I.; Kim, Y. H.; Tae, G.; Kundu, S. C. Silk fibroin nanoparticles for cellular uptake and control release. Int. J. Pharm. 2010, 388, 242–250.


Bessa, P. C.; Balmayor, E. R.; Hartinger, J.; Zanoni, G.; Dopler, D.; Meinl, A.; Banerjee, A.; Casal, M.; Redl, H.; Reis, R. L. et al. Silk fibroin microparticles as carriers for delivery of human recombinant bone morphogenetic protein-2: In vitro and in vivo bioactivity. Tissue Eng. Part C Methods 2010, 16, 937–945.


Wang, F.; Zhang, Y. Q. Bioconjugation of silk fibroin nanoparticles with enzyme and peptide and their characterization. Adv. Protein Chem. Struct. Biol. 2015, 98, 263–291.


Kim, W. J.; Islam, R.; Kim, B. S.; Cho, Y. D.; Yoon, W. J.; Baek, J. H.; Woo, K. M.; Ryoo, H. M. Direct delivery of recombinant Pin1 protein rescued osteoblast differentiation of Pin1-deficient cells. J. Cell. Physiol. 2017, 232, 2798–2805.


Huang, M.; Hu, M.; Song, Q. X.; Song, H. H.; Huang, J. L.; Gu, X.; Wang, X. L.; Chen, J.; Kang, T.; Feng, X. Y. et al. GM1-modified lipoprotein-like nanoparticle: Multifunctional nanoplatform for the combination therapy of Alzheimer’s disease. ACS Nano 2015, 9, 10801.


Zhang, Q.; Song, Q. X.; Gu, X.; Zheng, M. N.; Wang, A. T.; Jiang, G.; Huang, M.; Chen, H.; Qiu, Y.; Bo, B. et al. Multifunctional nanostructure RAP-RL rescues Alzheimer’s cognitive deficits through remodeling the neurovascular unit. Adv. Sci. 2021, 8, 2001918.


Wang, H. N.; Zou, Q.; Boerman, O. C.; Nijhuis, A. W. G.; Jansen, J. A.; Li, Y. B.; Leeuwenburgh, S. C. G. Combined delivery of BMP-2 and bFGF from nanostructured colloidal gelatin gels and its effect on bone regeneration in vivo. J. Control. Release 2013, 166, 172–181.


Ortiz-Guerrero, J. M.; Polanco, M. C.; Murillo, F. J.; Padmanabhan, S.; Elías-Arnanz, M. Light-dependent gene regulation by a coenzyme B12-based photoreceptor. Proc. Natl. Acad. Sci. USA 2011, 108, 7565–7570.


Wang, R.; Yang, Z. G; Luo, J. R.; Hsing, I. M.; Sun, F. B12-dependent photoresponsive protein hydrogels for controlled stem cell/protein release. Proc. Natl. Acad. Sci. USA 2017, 114, 5912–5917.


Bessa, P. C.; Machado, R.; Nürnberger, S.; Dopler, D.; Banerjee, A.; Cunha, A. M.; Rodríguez-Cabello, J. C.; Redl, H.; Van Griensven, M.; Reis, R. L. et al. Thermoresponsive self-assembled elastin-based nanoparticles for delivery of BMPs. J. Control. Release 2010, 142, 312–318.


Pokorski, J. K.; Hovlid, M. L.; Finn, M. G. Cell targeting with hybrid Qβ virus-like particles displaying epidermal growth factor. ChemBioChem 2011, 12, 2441–2447.


Matsumoto, R.; Hara, R.; Andou, T.; Mie, M. S. Y. S.; Kobatake, E. Targeting of EGF-displayed protein nanoparticles with anticancer drugs. J. Biomed. Mater. Res. B. 2014, 102, 1792–1798.


Li, X.; Pan, C.; Sun, P.; Peng, Z. H.; Feng, E. L.; Wu, J.; Wang, H. L.; Zhu, L. Orthogonal modular biosynthesis of nanoscale conjugate vaccines for vaccination against infection. Nano Res. 2022, 15, 1645–1653.


Raman, S.; Machaidze, G.; Lustig, A.; Aebi, U.; Burkhard, P. Structure-based design of peptides that self-assemble into regular polyhedral nanoparticles. Nanomed. Nanotechnol. Biol. Med. 2006, 2, 95–102.


Pimentel, T. A. P. F.; Yan, Z.; Jeffers, S. A.; Holmes, K. V.; Hodges, R. S.; Burkhard, P. Peptide nanoparticles as novel immunogens: Design and analysis of a prototypic severe acute respiratory syndrome vaccine. Chem. Biol. Drug Des. 2009, 73, 53–61.


Kanekiyo, M.; Wei, C. J.; Yassine, H. M.; McTamney, P. M.; Boyington, J. C.; Whittle, J. R. R.; Rao, S. S.; Kong, W. P.; Wang, L. S.; Nabel, G. J. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 2013, 499, 102–106.


Marcandalli, J.; Fiala, B.; Ols, S.; Perotti, M.; De Van Der Schueren, W.; Snijder, J.; Hodge, E.; Benhaim, M.; Ravichandran, R.; Carter, L. et al. Induction of potent neutralizing antibody responses by a designed protein nanoparticle vaccine for respiratory syncytial virus. Cell 2019, 176, 1420–1431.e17.


Boyoglu-Barnum, S.; Ellis, D.; Gillespie, R. A.; Hutchinson, G. B.; Park, Y. J.; Moin, S. M.; Acton, O. J.; Ravichandran, R.; Murphy, M.; Pettie, D. et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature 2021, 592, 623–628.


Deng, L.; Mohan, T.; Chang, T. Z.; Gonzalez, G. X.; Wang, Y.; Kwon, Y. M.; Kang, S. M.; Compans, R. W.; Champion, J. A.; Wang, B. Z. Double-layered protein nanoparticles induce broad protection against divergent influenza A viruses. Nat. Commun. 2018, 9, 359.


Lizotte, P. H.; Wen, A. M.; Sheen, M. R.; Fields, J.; Rojanasopondist, P.; Steinmetz, N. F.; Fiering, S. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nat. Nanotechnol. 2016, 11, 295–303.


Lebel, M. È.; Daudelin, J. F.; Chartrand, K.; Tarrab, E.; Kalinke, U.; Savard, P.; Labrecque, N.; Leclerc, D.; Lamarre, A. Nanoparticle adjuvant sensing by TLR7 enhances CD8+ T cell-mediated protection from Listeria monocytogenes infection. J. Immunol. 2014, 192, 1071–1078.


Jovčevska, I.; Muyldermans, S. The therapeutic potential of nanobodies. BioDrugs 2020, 34, 11–26.


Jiang, S. B.; Hillyer, C.; Du, L. Y. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol 2020, 41, 355–359.


Xiang, Y. F.; Nambulli, S; Xiao, Z. Y.; Liu, H; Sang, Z; Duprex, W. P.; Schneidman-Duhovny, D.; Zhang, C.; Shi, Y. Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2. Science 2020, 370, 1479–1484.


Lee, C.; Choi, M.; MacKay, J. A. Live long and active: Polypeptide-mediated assembly of antibody variable fragments. Adv. Drug Deliv. Rev. 2020, 167, 1–18.


Alam, M. K.; Brabant, M.; Viswas, R. S.; Barreto, K.; Fonge, H.; Ronald Geyer, C. A novel synthetic trivalent single chain variable fragment (tri-scFv) construction platform based on the SpyTag/SpyCatcher protein ligase system. BMC Biotechnol. 2018, 18, 55.


Beck, A.; Goetsch, L.; Dumontet, C.; Corvaïa, N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat. Rev. Drug. Discov. 2017, 16, 315–337.


Govindan, S. V.; Cardillo, T. M.; Sharkey, R. M.; Tat, F.; Gold, D. V.; Goldenberg, D. M. Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers. Mol. Cancer Ther. 2013, 12, 968–978.


Sandland, J.; Boyle, R. W. Photosensitizer antibody-drug conjugates: Past, present, and future. Bioconjugate Chem. 2019, 30, 975–993.


Hoffman, R. M. The multiple uses of fluorescent proteins to visualize cancer in vivo. Nat. Rev. Cancer 2005, 5, 796–806.


Guan, X. G.; Li, C.; Wang, D.; Sun, W. Q.; Gai, X. D. A tumor-targeting protein nanoparticle based on Tat peptide and enhanced green fluorescent protein. RSC Adv. 2016, 6, 9461–9464.


Matlashov, M. E.; Shcherbakova, D. M.; Alvelid, J.; Baloban, M.; Pennacchietti, F.; Shemetov, A. A.; Testa, I.; Verkhusha, V. V. A set of monomeric near-infrared fluorescent proteins for multicolor imaging across scales. Nat. Commun. 2020, 11, 239.


Yu, D.; Baird, M. A.; Allen, J. R.; Howe, E. S.; Klassen, M. P.; Reade, A.; Makhijani, K.; Song, Y. Q.; Liu, S. M.; Murthy, Z. et al. A naturally-monomeric infrared fluorescent protein for protein labeling in vivo. Nat. Methods 2015, 12, 763–765.


Zhang, J. R.; Li, B.; Zuo, J. L.; Gu, R.; Liu, B.; Ma, C.; Li, J. J.; Liu, K. An engineered protein adhesive with properties of tissue integration and controlled release for efficient cartilage repair. Adv. Healthc. Mater. 2021, 10, 2100109.


Wang, S. D.; Li, B.; Zhang, H. L.; Chen, J. Y.; Sun, X.; Xu, J.; Ren, T.; Zhang Y. Y.; Ma, C.; Guo, W. et al. Improving bioavailability of hydrophobic prodrugs through supramolecular nanocarriers based on recombinant proteins for osteosarcoma treatment. Angew. Chem., Int. Ed. 2021, 60, 11252.


Su, J. J.; Lu, S.; Jiang, S. J.; Li, B.; Liu, B.; Sun, Q. N.; Li, J. J.; Wang, F.; Wei, Y. Engineered protein photo-thermal hydrogels for outstanding in situ tongue cancer therapy. Adv. Mater. 2021, 33, 2100619.


Xiao, L. L.; Wang, Z. L.; Sun, Y.; Li, B.; Wu, B. H.; Ma, C.; Petrovskii V. S.; Gu, X. Q.; Chen, D.; Potemkin I. I. et al. An artificial phase-transitional underwater bioglue with robust and switchable adhesion performance. Angew. Chem., Int. Ed. 2021, 60, 12082–12089.


Kobayashi, M.; Squires, G. R.; Mousa, A.; Tanzer, M.; Zukor, D. J.; Antoniou, J.; Feige, U.; Poole, A. R. Role of interleukin-1 and tumor necrosis factor α in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum. 2005, 52, 128–135.


Nuki, G.; Bresnihan, B.; Bear, M. B.; McCabe, D. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: Extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002, 46, 2838–2846.


Shamji, M. F.; Betre, H.; Kraus, V. B.; Chen, J.; Chilkoti, A.; Pichika, R.; Masuda, K.; Setton, L. A. Development and characterization of a fusion protein between thermally responsive elastin-like polypeptide and interleukin-1 receptor antagonist: Sustained release of a local antiinflammatory therapeutic. Arthritis Rheum. 2007, 56, 3650–3661.


Cai, R.; Chen, C. Y. The Crown and the Scepter: Roles of the protein corona in nanomedicine. Adv. Mater. 2019, 31, 1805740.


Azizi, M.; Ghourchian, H.; Yazdian, F.; Bagherifam, S.; Bekhradnia, S.; Nyström, B. Anti-cancerous effect of albumin coated silver nanoparticles on MDA-MB 231 human breast cancer cell line. Sci. Rep. 2017, 7, 5178.


Yousefpour, P.; Ahn, L.; Tewksbury, J.; Saha, S.; Costa, S. A.; Bellucci, J. J.; Li, X. H.; Chilkoti, A. Conjugate of doxorubicin to albumin-binding peptide outperforms aldoxorubicin. Small 2019, 15, 1804452.


Schöttler, S.; Becker, G.; Winzen, S.; Steinbach, T.; Mohr, K.; Landfester, K.; Mailänder, V.; Wurm, F. R. Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. Nat. Nanotechnol. 2016, 11, 372–377.


Zhang, Z.; Guan, J.; Jiang, Z. X.; Yang, Y.; Liu, J. C.; Hua, W.; Mao, Y.; Li, C.; Lu, W. Y.; Qian, J. et al. Brain-targeted drug delivery by manipulating protein corona functions. Nat. Commun. 2019, 10, 3561.


Chen, J. Q.; Qi, J.; Chen, C.; Chen, J. H.; Liu, L. J.; Gao, R. K.; Zhang, T. T.; Song, L.; Ding, D.; Zhang, P. et al. Tocilizumab-conjugated polymer nanoparticles for NIR-II photoacoustic-imaging-guided therapy of rheumatoid arthritis. Adv. Mater. 2020, 32, 2003399.

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Publication history

Received: 03 October 2021
Revised: 20 November 2021
Accepted: 25 December 2021
Published: 07 March 2022
Issue date: June 2022


© Tsinghua University Press 2022



This research was supported by the National Key Research and Development Program of China (Nos. 2020YFA0908900, 2018YFA0902600, and 2020YFA0712102), the National Natural Science Foundation of China (Nos. 21877104, 21834007, 22107097, 21878258, 22020102003, and 22125701), K. C. Wong Education Foundation (No. GJTD-2018-09), and the Youth Innovation Promotion Association of the Chinese Academy (CAS, No. 2021226).