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However, antibiotics are losing efficacy due to the emergence of multidrug\u2010resistant pathogens. Here, we reported a bioresponsive nanoparticle with antimicrobial activity and targeting effect to bypass the antimicrobial resistance and to improve the bacterial infections treatment. We established a mini library of quaternary ammonium compounds, and screened the N\u2010benzyl\u2010N\u2010(n\u2010(4\u2010formyl\u20103,5\u2010dimethoxyphenoxy)decyl)\u2010N,N,N,N\u2010tetramethylhexane\u20101,6\u2010diaminium (BTA\u201010) that enabled high antimicrobial activity in vitro and safety in vivo, which was selected to conjugate with the poly(ethylene glycol) (PEG) via pH\u2010responsive bond to synthesize amphiphilic copolymer for preparation of polymeric micelle, followed by decorating with anti\u2010ICAM\u20101 as targeting ligand via click chemistry, resulting in bioresponsive nanoparticle (NPs\u2010anti\u2010ICAM\u20101). The anti\u2010inflammatory drug TPCA\u20101 was physically loaded to enhance the therapeutic efficacy, to prepare the final therapeutic (TPCA\u20101@NPs\u2010anti\u2010ICAM\u20101). Upon intravenous injection, TPCA\u20101@NPs\u2010anti\u2010ICAM\u20101 can specifically target to the site of infection, and release the cargos (BTA\u201010 and TPCA\u20101) by responding to acids in the infection microenvironment. The in vivo studies demonstrated that TPCA\u20101@NPs\u2010anti\u2010ICAM\u20101 showed high therapeutic efficacy for acute lung infection and peritonitis in mouse. In summary, we reported a de novo\u2010designed bioresponsive nanoparticle with antimicrobial activity, offering a promising approach to combat bacterial infections.<\/jats:p>","DOI":"10.1002\/adhm.202505683","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:33:11Z","timestamp":1770899591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["De Novo Development of Bioresponsive Nanoparticles With Antimicrobial Activity to Treat Bacterial Infections"],"prefix":"10.1002","volume":"15","author":[{"given":"Liang","family":"Zhao","sequence":"first","affiliation":[{"name":"Institute of Biopharmaceutical and Health Engineering Shenzhen International Graduate School Tsinghua University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical and Health 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