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Our next-generation antibiotics should aim for a different antimicrobial mechanism that is less conducive to AMR, a wider therapeutic window tolerant to drug titration, and a quicker deactivation strategy responsive to environmental stimuli. Membrane-active antimicrobials (MAAs) have the potential to thwart AMR, but the lipophilicity of current MAAs gives rise to their broad-spectrum cytotoxicity. Here, we show that biological nanoparticles, such as cyclodextrin and phytoglycogen, can be transformed into potent MAAs with low cytotoxicity by grafting them with hydrophilic polymer brushes. In service, these hydrophilic nanoantibiotics kill bacteria by inducing pore formation exclusively on microbial membranes rich in negative curvature lipids, a bactericidal mode less likely to incur AMR. After service, they are degraded and deactivated by biomass recycling enzymes that are abundant in ecosystems. This study illuminates a new paradigm to combat AMR with hydrophilic and eco-friendly membrane-active antibiotics derived from biological nanoparticles.<\/jats:p>","DOI":"10.1021\/acsnanoscienceau.6c00025","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T23:35:00Z","timestamp":1781825700000},"page":"606-621","source":"Crossref","is-referenced-by-count":0,"title":["Combating\nAntimicrobial Resistance with Hydrophilic\nand Eco-Friendly Membrane-Active Antibiotics Derived from Biological\nNanoparticles"],"prefix":"10.1021","volume":"6","author":[{"given":"Wan","family":"Zheng","sequence":"first","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Lubbock, Texas, United States, 79430"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Ma","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Lubbock, Texas, United States, 79430"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Dutcher","sequence":"additional","affiliation":[{"name":"University of Guelph , , , ,","place":["Guelph, Ontario, Canada, N1G 2W1"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0864-9106","authenticated-orcid":true,"given":"Hongjun","family":"Liang","sequence":"additional","affiliation":[{"name":"Texas Tech University Health Sciences Center , , , ,","place":["Lubbock, Texas, United States, 79430"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"issue":"3","key":"2026081909073625300_cit1","first-page":"226","article-title":"On the Antibacterial\nAction of Cultures of a Penicillium, with Special Reference to their\nUse in the Isolation of B. influenz\u00e6","volume":"10","author":"Fleming","year":"1929","journal-title":"Br.\nJ. Exp. Pathol"},{"issue":"3","key":"2026081909073625300_cit2","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1093\/jhmas\/jrh091","article-title":"Waksman, and the balance of credit for discovery","volume":"59","author":"Kingston","year":"2004","journal-title":"J. Hist. Med. Allied Sci"},{"issue":"D1","key":"2026081909073625300_cit3","doi-asserted-by":"publisher","first-page":"D517","DOI":"10.1093\/nar\/gkz935","article-title":"CARD 2020: antibiotic resistome surveillance with the\ncomprehensive antibiotic resistance database","volume":"48","author":"Alcock","year":"2019","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"2026081909073625300_cit4","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/nrmicro3380","article-title":"Molecular\nmechanisms of antibiotic resistance","volume":"13","author":"Blair","year":"2015","journal-title":"Nat. Rev.\nMicrobiol."},{"issue":"6","key":"2026081909073625300_cit5","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/j.cell.2007.03.004","article-title":"Molecular mechanisms of antibacterial multidrug resistance","volume":"128","author":"Alekshun","year":"2007","journal-title":"Cell Rev."},{"issue":"9214","key":"2026081909073625300_cit6","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1016\/S0140-6736(00)02173-5","article-title":"FDA approves\nfirst drug in new class of antibiotics","volume":"355","author":"Senior","year":"2000","journal-title":"The\nLancet"},{"issue":"9277","key":"2026081909073625300_cit7","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S0140-6736(01)05410-1","article-title":"Linezolid resistance in a clinical isolate of Staphylococcus\naureus","volume":"358","author":"Tsiodras","year":"2001","journal-title":"The Lancet"},{"issue":"15","key":"2026081909073625300_cit8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1717295115","article-title":"Global increase\nand geographic convergence in antibiotic consumption between 2000\nand 2015","volume":"115","author":"Klein","year":"2018","journal-title":"Proc. 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Dev."},{"key":"2026081909073625300_cit15","doi-asserted-by":"publisher","first-page":"129628","DOI":"10.1016\/j.jhazmat.2022.129628","article-title":"Global\nreview of macrolide antibiotics in the aquatic environment:\nSources, occurrence, fate, ecotoxicity, and risk assessment","volume":"439","author":"Li","year":"2022","journal-title":"J. Hazard. Mater."},{"key":"2026081909073625300_cit16","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.jes.2020.05.030","article-title":"A survey of sub-inhibitory concentrations\nof antibiotics in the environment","volume":"99","author":"Chow","year":"2021","journal-title":"J. Environ.\nSci."},{"issue":"5","key":"2026081909073625300_cit17","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/s41579-021-00649-x","article-title":"Antibiotic resistance in the environment","volume":"20","author":"Larsson","year":"2022","journal-title":"Nat. Rev. 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Biotechnol."},{"issue":"9","key":"2026081909073625300_cit37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0073812","article-title":"Nature-Inspired Antimicrobial\nPolymers - Assessment\nof Their Potential for Biomedical Applications","volume":"8","author":"Al-Ahmad","year":"2013","journal-title":"PLoS One"},{"issue":"1","key":"2026081909073625300_cit38","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ijantimicag.2015.11.005","article-title":"Towards a\ndefinition\nof daptomycin optimal dose: Lessons learned from experimental and\nclinical data","volume":"47","author":"Senneville","year":"2016","journal-title":"Int. J. Antimicrob. 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Healthcare\nMater."},{"issue":"21","key":"2026081909073625300_cit53","doi-asserted-by":"publisher","first-page":"1800627","DOI":"10.1002\/adhm.201800627","article-title":"Architectural Effects\nof Star-Shaped \u201cStructurally Nanoengineered Antimicrobial Peptide\nPolymers\u201d (SNAPPs) on Their Biological Activity","volume":"7","author":"Shirbin","year":"2018","journal-title":"Adv. Healthcare Mater."},{"key":"2026081909073625300_cit54","doi-asserted-by":"publisher","first-page":"112698","DOI":"10.1016\/j.eurpolymj.2023.112698","article-title":"Shape matters: Effect of amphiphilic polymer topology on antibacterial\nactivity and hemocompatibility","volume":"205","author":"Aquib","year":"2024","journal-title":"Eur. Polym.\nJ."},{"issue":"1","key":"2026081909073625300_cit55","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1021\/acs.biomac.4c00882","article-title":"Cationic Star\nPolymers Obtained by\nthe Arm-First Approach-Influence of Arm Number and Positioning of\nCationic Units on Antimicrobial Activity","volume":"26","author":"Laroque","year":"2025","journal-title":"Biomacromolecules"},{"issue":"10","key":"2026081909073625300_cit56","doi-asserted-by":"publisher","first-page":"2312651","DOI":"10.1002\/adfm.202312651","article-title":"Anisotropy in Antimicrobial\nBottle Brush Copolymers and Its Influence on Biological Activity","volume":"34","author":"Lehnen","year":"2024","journal-title":"Adv. Funct. 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