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Antimicrobial proteins (AMPs) are a promising alternative for treating MDR bacterial infections, but their effectiveness is limited by instability, narrow\u2010spectrum activity, and poor pharmacokinetics. Although conjugated or complexed cationic polymers can enhance the antimicrobial spectrum and potency of AMPs, they also cause AMPs to interact excessively with biomacromolecules in vivo, potentially reducing their therapeutic efficacy. Herein, screening of an ultra\u2010acid\u2010sensitive diblock copolymer\u2010lysozyme conjugate to self\u2010assemble into LPOBE micelle with enhanced stability. In acidic conditions, protonated LPOBE with low positive charge showed great serum protein\u2010nonfouling ability and yielded highly effective bactericidal activity, achieving a 99.9% reduction in three MDR GN ESKAPE strains. Inhalation delivery can achieve high local concentrations of AMPs, but mucus in the lower respiratory tract impedes their penetration into infected areas due to the positive charge of AMPs. Furthermore, bacterial pneumonia is often accompanied by excessive inflammation. Therefore, we further developed a \u2018One\u2010Stone\u2010Two\u2010Birds\u2019 strategy by loading sodium butyrate (NaBu), a small molecule immunomodulator, to form negatively charged LPOBEN, which improves both mucus penetration and anti\u2010inflammatory effects of LPOBE. This system offers a novel theoretical foundation to develop high\u2010performance AMP\u2010based nanomedicines for clinical therapy.<\/jats:p>","DOI":"10.1002\/adhm.202504626","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T07:41:02Z","timestamp":1765438862000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhaled Micelle of Antimicrobial Protein\u2010Polymer Conjugate with Less Positive Charge Leads to Better Mucus Penetration and Enhanced Gram\u2010Negative Pneumonia Therapy"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6637-0340","authenticated-orcid":false,"given":"Fei","family":"Duan","sequence":"first","affiliation":[{"name":"Department of Nanomedicine Translational Medicine Research Center, &amp; Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices Naval Medical University  Shanghai 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