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In this study, a series of potent nano\u2010short peptides are engineered based on the short peptide anti\u2010enzymolysis motif \u201cR\n                    <jats:sup>D<\/jats:sup>\n                    RRP\u201d by introducing different hydrophobic groups using different strategies. The validity of the self\u2010assembly system triggered by naphthyl tail anchoring is confirmed through a comprehensive analysis of the bioactivity and nanoproperties of these nano\u2010short peptides. The naphthyl tail\u2010anchored N\n                    <jats:sub>4<\/jats:sub>\n                    peptide (Nal\u2010Nal\u2010Nal\u2010Nal\u2010R\n                    <jats:sup>D<\/jats:sup>\n                    \u2010R\u2010R\u2010P) could self\u2010assemble into nanofibers in aqueous solutions, exhibiting potent and broad\u2010spectrum antimicrobial activity with excellent biocompatibility (Geometric Mean of the Minimum Inhibitory Concentration (GM\n                    <jats:sub>MIC<\/jats:sub>\n                    ) = 5.04, Geometric Mean of the Selectivity Index (GM\n                    <jats:sub>SI<\/jats:sub>\n                    ) = 50.8) and remarkable biostability against physiological challenges (salt concentrations, serum components, and various proteases). More importantly, the low resistance propensity for N\n                    <jats:sub>4<\/jats:sub>\n                    is attributed to multiple antimicrobial mechanisms combining physical membrane\u2010breaking and energy metabolism disruption. Its efficacy is substantiated in both\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    (\n                    <jats:italic>E. coli<\/jats:italic>\n                    ) induced murine peritonitis\u2010sepsis and Methicillin\u2010Resistant\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    (\n                    <jats:italic>MRSA)<\/jats:italic>\n                    mediated skin infection models in mice. In summary, these findings advance the design of AMPs with enhanced protease resistance and the development of peptide\u2010based nanomaterials for biomedical applications.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508854","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T19:13:36Z","timestamp":1757963616000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Utilizing Proteolytic\u2010Resistant Nano\u2010Short Peptide Based on Naphthyl Tail\u2010Anchored to Combat Bacterial Infections"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3169-0136","authenticated-orcid":false,"given":"Xi","family":"Yan","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology Northeast Agricultural University  Harbin 150030 The People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinfeng","family":"Lyu","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Northeast Agricultural University  Harbin 150030 The People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Northeast Agricultural University  Harbin 150030 The People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Ren","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Northeast Agricultural University  Harbin 150030 The People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Northeast Agricultural University  Harbin 150030 The People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Licong","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Northeast Agricultural University  Harbin 150030 The People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshan","family":"Shan","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology Northeast Agricultural University  Harbin 150030 The People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30753-3"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612828666220608120238"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10388"},{"key":"e_1_2_9_4_1","first-page":"63","volume":"15","author":"Komolafe O. 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