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Here, we present an \u201cintegrated offense\u2012defense\u201d strategy in which binding to mammalian cells is inhibited (defense) but bacterial membrane insertion is improved (offense), effectively decoupling antimicrobial potency from host cytotoxicity. We demonstrated that nano\u2010AMPs with moderate surface potentials (\u223c+20\u00a0mV) preferentially bind to bacteria and exhibit minimal interactions with mammalian cells because of the inherent charge disparity between bacterial and mammalian cell membranes. Experimental and theoretical analysis revealed that systematic sequence engineering resulted in peptide nanofibers with loose molecular packing and high exposure of hydrophobic residues. The optimized nano\u2010AMP exhibited potent antimicrobial activity (MIC of 5\u223c6 \u00b5M) and exceptional biosafety (therapeutic index TI = HC\n                    <jats:sub>10<\/jats:sub>\n                    \/ MIC &gt; 30; selectivity index SI = IC\n                    <jats:sub>20<\/jats:sub>\n                    \/ MIC&gt; 50). A murine skin wound infection model confirmed the antimicrobial efficacy of this peptide, which reduced the bacterial burden and promoted wound healing.\n                  <\/jats:p>","DOI":"10.1002\/anie.5517893","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T08:39:43Z","timestamp":1776328783000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Self\u2010Assembling Nano\u2010Antimicrobial Oligopeptides With Dual Offense\u2013Defense Functions for Synchronously Achieving High Activity and Biosafety"],"prefix":"10.1002","volume":"65","author":[{"given":"He","family":"Zhao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Tian","sequence":"additional","affiliation":[{"name":"College of Basic 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