Graphical Abstract
![](https://wqketang.oss-cn-beijing.aliyuncs.com/unzip/large-zip/zip-2a02756c-9a3e-46eb-b900-8aa2a7a59dfe/5856/files/5856-TOC.jpg?Expires=1725757464&OSSAccessKeyId=STS.NSssK71aLjDMY9SbRgGRGskMT&Signature=fxyYaB2P2T%2FbDbjJFXk0lJ23ha0%3D&security-token=CAISywJ1q6Ft5B2yfSjIr5DGOPGD3L5t3YamWx%2FihlIyS91rnK7mtjz2IHtKenhsBOsbtfk1mG5W5%2FgZlqJ9SptIAEfJa9d99Myjb%2F9FltCT1fau5Jko1beHewHKeTOZsebWZ%2BLmNqC%2FHt6md1HDkAJq3LL%2Bbk%2FMdle5MJqP%2B%2FUFB5ZtKWveVzddA8pMLQZPsdITMWCrVcygKRn3mGHdfiEK00he8TouufTinpHMskGA1Aell7Mvyt6vcsT%2BXa5FJ4xiVtq55utye5fa3TRYgxowr%2Fwo0v0YpGya5YzHXwcPskvdKZbo78UqLQlla6w%2BGqFJqvPxr%2Fp8t%2Fx5fWJKAezhVgs8cVM8JOjIqKOscIsixo262SmqFV55c8Fdm%2BgUooJVgIMhTnduUfAPJAGOxzJitP%2BUVGGphr60TEnBL4rB5MUctfzRpwT64j3UTzDnGoABhFRSspTLrn9GrEN9pQYzC6eepGdfWDQh3fr5hA1VnwVUJMCz%2BNQEDWKceF%2FnEjWVMtfbvqYxuyhSCmIMMyh5bEREEKEiD%2BFVv4ZfsqnV7hQy5w6HhIkN8kZzP6L0zPvPgkBLOtdMDeDxhf8dVPrCSG4etXHjxcwUaRVb3ZR7Yu8gAA%3D%3D)
Discover the SciOpen Platform and Achieve Your Research Goals with Ease.
Even the potential of T cell-mimicking nanotrap for long term viral control due to its overcoming of human immunodeficiency virus (HIV) genetic diversity and viral resistance, the robust HIV inhibition was not expected because these nanotraps displayed no obvious advantages compared with the infinite host cells. Herein, a glycoprotein 120 (gp120)-targeting polypeptide UM15 reinforced lymphocyte-mimicking nanotrap was constructed, and its improved HIV-1 inhibiting efficacy was validated. According to the results, the constructed nanotraps exhibited evident escaping ability from uptake of the mononuclear phagocyte system and highly improved binding ability with gp120 proteins. The constructed nanotraps neutralized all tested HIV-1 pseudo typed viruses with IC80 of 21.0 μg/mL, and inhibited both X4-tropic and R5-tropic HIV-1 with IC80 of 34.4 and 20.6 μg/mL, respectively. Approximately 40% of gp120 was observed to be shed from pseudo virus, and above 40% bystander T cells were prevented from gp120-induced death by the constructed nanotraps. The safety of the constructed nanotraps was confirmed both in vitro and in mice. Therefore, the constructed nanotraps could specifically neutralize free HIV-1, selectively bind with gp120 expressing HIV-1 infected cells, cause gp120 shedding, inhibit gp120-induced bystander T cell killing on the premise of safety, and were considered as promising therapeutic agents for precise inhibition of HIV.
Mishra, V.; Kesharwani, P.; Jain, N. K. siRNA nanotherapeutics: A Trojan horse approach against HIV. Drug Discov. Today 2014, 19, 1913–1920.
Wei, X. L.; Zhang, G.; Ran, D. N.; Krishnan, N.; Fang, R. H.; Gao, W. W.; Spector, S. A.; Zhang, L. F. T-cell-mimicking nanoparticles can neutralize HIV infectivity. Adv. Mater 2018, 30, 1802233.
Gaffney, A.; Nangarlia, A.; Ang, C. G.; Gossert, S.; Rashad Ahmed, A. A.; Hossain, A.; Abrams, C. F.; Smith III, A. B.; Chaiken, I. HIV-1 env-dependent cell killing by bifunctional small-molecule/peptide conjugates. ACS Chem. Biol. 2021, 16, 193–204.
Adesina, S. K.; Akala, E. O. Nanotechnology approaches for the delivery of exogenous siRNA for HIV therapy. Mol. Pharm. 2015, 12, 4175–4187.
Hoffmann, M. A. G.; Bar-On, Y.; Yang, Z.; Gristick, H. B.; Gnanapragasam, P. N. P.; Vielmetter, J.; Nussenzweig, M. C.; Bjorkman, P. J. Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells. Proc. Natl. Acad. Sci. U S A 2020, 117, 18719–18728.
Cillo, A. R.; Mellors, J. W. Which therapeutic strategy will achieve a cure for HIV-1. Curr. Opin. Virol. 2016, 18, 14–19.
Arimori, T.; Ikemura, N.; Okamoto, T.; Takagi, J.; Standley, D. M.; Hoshino, A. Engineering ACE2 decoy receptors to combat viral escapability. Trends Pharmacol. Sci. 2022, 43, 838–851.
Campbell, G. R.; Zhuang, J.; Zhang, G.; Landa, I.; Kubiatowicz, L. J.; Dehaini, D.; Fang, R. H.; Zhang, L. F.; Spector, S. A. CD4+ T cell-mimicking nanoparticles encapsulating DIABLO/SMAC mimetics broadly neutralize HIV-1 and selectively kill HIV-1-infected cells. Theranostics 2021, 11, 9009–9021.
Chen, M.; Rosenberg, J.; Cai, X. L.; Lee, A. C. H.; Shi, J. Y.; Nguyen, M.; Wignakumar, T.; Mirle, V.; Edobor, A. J.; Fung, J. et al. Nanotraps for the containment and clearance of SARS-CoV-2. Matter 2021, 4, 2059–2082.
Chakravarty, M.; Vora, A. Nanotechnology-based antiviral therapeutics. Drug Deliv. Transl. Res. 2021, 11, 748–787.
Faria, M. J.; Lopes, C. M.; das Neves, J.; Lúcio, M. Lipid nanocarriers for anti-HIV therapeutics: A focus on physicochemical properties and biotechnological advances. Pharmaceutics 2021, 13, 1294.
Nai, J. X.; Zhang, J. B.; Li, J. X.; Li, H.; Yang, Y.; Yang, M. Y.; Wang, Y. L.; Gong, W.; Li, Z. P.; Li, L. et al. Macrophage membrane- and cRGD-functionalized thermosensitive liposomes combined with CPP to realize precise siRNA delivery into tumor cells. Mol. Ther. Nucleic Acids 2022, 27, 349–362.
Song, H. Y.; Chen, X. H.; Hao, Y. J.; Wang, J.; Xie, Q. P.; Wang, X. Nanoengineering facilitating the target mission: Targeted extracellular vesicles delivery systems design. J. Nanobiotechnol. 2022, 20, 431.
Ramírez-Chacón, A.; Betriu-Méndez, S.; Bartoló-Ibars, A.; González, A.; Martí, M.; Juan, M. Ligand-based CAR-T cell: Different strategies to drive T cells in future new treatments. Front. Immunol. 2022, 13, 932559.
Cevaal, P. M.; Ali, A.; Czuba-Wojnilowicz, E.; Symons, J.; Lewin, S. R.; Cortez-Jugo, C.; Caruso, F. In vivo T cell-targeting nanoparticle drug delivery systems: Considerations for rational design. ACS Nano 2021, 15, 3736–3753.
Kozma, G. T.; Shimizu, T.; Ishida, T.; Szebeni, J. Anti-PEG antibodies: Properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Adv. Drug Deliv. Rev. 2020, 154–155, 163–175.
Rastogi, M.; Saha, R. N.; Alexander, A.; Singhvi, G.; Puri, A.; Dubey, S. K. Role of stealth lipids in nanomedicine-based drug carriers. Chem. Phys. Lipids 2021, 235, 105036.
Shi, D.; Beasock, D.; Fessler, A.; Szebeni, J.; Ljubimova, J. Y.; Afonin, K. A.; Dobrovolskaia, M. A. To PEGylate or not to PEGylate: Immunological properties of nanomedicine's most popular component, polyethylene glycol and its alternatives. Adv. Drug Deliv. Rev. 2022, 180, 114079.
Kroll, A. V.; Jiang, Y.; Zhou, J. R.; Holay, M.; Fang, R. H.; Zhang, L. F. Biomimetic nanoparticle vaccines for cancer therapy. Adv. Biosyst. 2019, 3, 1800219.
Wu, H. H.; Jiang, X. C.; Li, Y. S.; Zhou, Y.; Zhang, T. Y.; Zhi, P.; Gao, J. Q. Engineering stem cell derived biomimetic vesicles for versatility and effective targeted delivery. Adv. Funct. Mater. 2020, 49, 2006169.
Le, Q. V.; Lee, J.; Lee, H.; Shim, G.; Oh, Y. K. Cell membrane-derived vesicles for delivery of therapeutic agents. Acta Pharm. Sin. B 2021, 11, 2096–2113.
Gao, C. H.; Chu, X. Y.; Gong, W.; Zheng, J. P.; Xie, X. Y.; Wang, Y. L.; Yang, M. Y.; Li, Z. P.; Gao, C. S.; Yang, Y. Neuron tau-targeting biomimetic nanoparticles for curcumin delivery to delay progression of Alzheimer's disease. J. Nanobiotechnol. 2020, 18, 71.
Fu, S. Y.; Liang, M.; Wang, Y. L.; Cui, L.; Gao, C. H.; Chu, X. Y.; Liu, Q. Q.; Feng, Y.; Gong, W.; Yang, M. Y. et al. Dual-modified novel biomimetic nanocarriers improve targeting and therapeutic efficacy in glioma. ACS Appl. Mater. Interfaces 2019, 11, 1841–1854.
Liu, L. Z.; Pan, D. Y.; Chen, S.; Martikainen, M. V.; Kårlund, A.; Ke, J.; Pulkkinen, H.; Ruhanen, H.; Roponen, M.; Käkelä, R. et al. Systematic design of cell membrane coating to improve tumor targeting of nanoparticles. Nat. Commun 2022, 13, 6181.
Zhang, G.; Campbell, G. R.; Zhang, Q. Z.; Maule, E.; Hanna, J.; Gao, W. W.; Zhang, L. F.; Spector, S. A. CD4+ T cell-mimicking nanoparticles broadly neutralize HIV-1 and suppress viral replication through autophagy. mBio 2020, 11, e00903-20.
Lee, B.; Sharron, M.; Montaner, L. J.; Weissman, D.; Doms, R. W. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc. Natl. Acad. Sci. USA 1999, 96, 5215–5220.
Umashankara, M.; McFadden, K.; Zentner, I.; Schön, A.; Rajagopal, S.; Tuzer, F.; Kuriakose, S. A.; Contarino, M.; LaLonde, J.; Freire, E. et al. The active core in a triazole peptide dual-site antagonist of HIV-1 gp120. ChemMedChem 2010, 5, 1871–1879.
Aneja, R.; Rashad, A. A.; Li, H. Y.; Kalyana Sundaram, R. V.; Duffy, C.; Bailey, L. D.; Chaiken, I. Peptide triazole inactivators of HIV-1 utilize a conserved two-cavity binding site at the junction of the inner and outer domains of Env gp120. J. Med. Chem. 2015, 58, 3843–3858.
He, Z. H.; Zhang, Y. T.; Feng, N. P. Cell membrane-coated nanosized active targeted drug delivery systems homing to tumor cells: A review. Mater. Sci. Eng. C 2020, 106, 110298.
Tang, Y. X.; Wang, X. Y.; Li, J.; Nie, Y.; Liao, G. J.; Yu, Y.; Li, C. Overcoming the reticuloendothelial system barrier to drug delivery with a "Don't-Eat-Us" strategy. ACS Nano 2019, 13, 13015–13026.
Wang, Y.; Zhang, K.; Li, T. H.; Maruf, A.; Qin, X.; Luo, L.; Zhong, Y.; Qiu, J. H.; McGinty, S.; Pontrelli, G. et al. Macrophage membrane functionalized biomimetic nanoparticles for targeted anti-atherosclerosis applications. Theranostics 2021, 11, 164–180.
Hu, C. M. J.; Fang, R. H.; Luk, B. T.; Chen, K. N. H.; Carpenter, C.; Gao, W. W.; Zhang, K.; Zhang, L. F. 'Marker-of-self' functionalization of nanoscale particles through a top-down cellular membrane coating approach. Nanoscale 2013, 5, 2664–2668.
Pustylnikov, S.; Dave, R. S.; Khan, Z. K.; Porkolab, V.; Rashad, A. A.; Hutchinson, M.; Fieschi, F.; Chaiken, I.; Jain, P. Short communication: Inhibition of DC-SIGN-Mediated HIV-1 infection by complementary actions of dendritic cell receptor antagonists and Env-targeting virus inactivators. AIDS Res. Hum. Retroviruses 2016, 32, 93–100.
Rashad, A. A.; Song, L. R.; Holmes, A. P.; Acharya, K.; Zhang, S. Y.; Wang, Z. L.; Gary, E.; Xie, X.; Pirrone, V.; Kutzler, M. A. et al. Bifunctional chimera that coordinately targets human immunodeficiency virus 1 envelope gp120 and the host-cell CCR5 coreceptor at the virus-cell interface. J. Med. Chem. 2018, 61, 5020–5033.
Biorn, A. C.; Cocklin, S.; Madani, N.; Si, Z. H.; Ivanovic, T.; Samanen, J.; Van Ryk, D. I.; Pantophlet, R.; Burton, D. R.; Freire, E. et al. Mode of action for linear peptide inhibitors of HIV-1 gp120 interactions. Biochemistry 2004, 43, 1928–1938.
Bastian, A. R.; Contarino, M.; Bailey, L. D.; Aneja, R.; Moreira, D. R.; Freedman, K.; McFadden, K.; Duffy, C.; Emileh, A.; Leslie, G. et al. Interactions of peptide triazole thiols with Env gp120 induce irreversible breakdown and inactivation of HIV-1 virions. Retrovirology 2013, 10, 153.
Chaiken, I.; Rashad, A. A. Peptide triazole inactivators of HIV-1: How do they work and what is their potential. Future Med. Chem. 2015, 7, 2305–2310.
Garg, H.; Mohl, J.; Joshi, A. HIV-1 induced bystander apoptosis. Viruses 2012, 4, 3020–3043.
Dockrell, D. H. Apoptotic cell death in the pathogenesis of infectious diseases. J. Infect. 2001, 42, 227–234.
Trushin, S. A.; Algeciras-Schimnich, A.; Vlahakis, S. R.; Bren, G. D.; Warren, S.; Schnepple, D. J.; Badley, A. D. Glycoprotein 120 binding to CXCR4 causes p38-dependent primary T cell death that is facilitated by, but does not require cell-associated CD4. J. Immunol. 2007, 178, 4846–4853.
Luo, X. Y.; Mouquet, H.; Schwartz, O.; Greene, W. C. Bystander CD4 T-cell death is inhibited by broadly neutralizing anti-HIV antibodies only at levels blocking cell-to-cell viral transmission. J. Biol. Chem. 2021, 297, 101098.
Richard, J.; Veillette, M.; Ding, S. L.; Zoubchenok, D.; Alsahafi, N.; Coutu, M.; Brassard, N.; Park, J.; Courter, J. R.; Melillo, B. et al. Small CD4 mimetics prevent HIV-1 uninfected bystander CD4+ T cell killing mediated by antibody-dependent cell-mediated cytotoxicity. eBioMedicine 2016, 3, 122–134.
Pu, J.; Wang, Q.; Xu, W.; Lu, L.; Jiang, S. B. Development of protein-and peptide-based HIV entry inhibitors targeting gp120 or gp41. Viruses 2019, 11, 705.
Düzgüneş, N.; Fernandez-Fuentes, N.; Konopka, K. Inhibition of viral membrane fusion by peptides and approaches to peptide design. Pathogens 2021, 10, 1599.
Li, L.; Hu, X. Q.; Zhang, M.; Ma, S. Y.; Yu, F. L.; Zhao, S. Q.; Liu, N.; Wang, Z. Y.; Wang, Y.; Guan, H. et al. Dual tumor-targeting nanocarrier system for siRNA delivery based on pRNA and modified chitosan. Mol. Ther. Nucleic Acids 2017, 8, 169–183.
Ma, R.; Nai, J. X.; Zhang, J. B.; Li, Z. P.; Xu, F. H.; Gao, C. S. Co-delivery of CPP decorated doxorubicin and CPP decorated siRNA by NGR-modified nanobubbles for improving anticancer therapy. Pharm. Dev. Technol. 2021, 26, 634–646.
Gao, Y.; Nai, J. X.; Yang, Z. B.; Zhang, J. B.; Ma, S. Y.; Zhao, Y. M.; Li, H.; Li, J. X.; Yang, Y.; Yang, M. Y. et al. A novel preparative method for nanoparticle albumin-bound paclitaxel with high drug loading and its evaluation both in vitro and in vivo. PLoS One 2021, 16, e0250670.