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Here, we demonstrate that surface chirality of nanomaterials serves as an independent parameter to disrupt this loop through targeted metabolic interference. Using gold nanoparticles (GNPs) as a model, we show that D\u2010chiral GNPs (GNP\u2010D) exhibit superior efficacy over their L\u2010enantiomers (GNP\u2010L) in repressing bacterial basal metabolism and impeding near\u2010surface motility. Integration of transcriptomic profiling and molecular dynamics identifies the mannitol\u2010specific phosphotransferase transporter MtlA as a pivotal target, where GNP\u2010D induces enhanced structural perturbations at functional residues compared to GNP\u2010L. In a murine infection model, GNP\u2010D significantly reduces bacterial burden and accelerates wound closure while repolarizing the wound microenvironment from a persistent pro\u2010inflammatory state toward a pro\u2010resolving and regenerative phenotype. Notably, genetic ablation of\n                    <jats:italic>mtlA<\/jats:italic>\n                    abrogates the chiral bias across all metabolic and immune readouts, providing evidence that this advantage is mediated via the MtlA\/PTS axis. These results establish a \u201cchirality\u2010membrane\u2010protein coupling\u201d framework for the rational design of targeted antimicrobial and immunomodulatory nanomedicines.\n                  <\/jats:p>","DOI":"10.1002\/smll.74522","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:22:01Z","timestamp":1784701321000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Surface Chirality Enables MtlA\u2010Dependent Antibacterial Activity and Immune Remodeling by Gold Nanoparticles"],"prefix":"10.1002","volume":"22","author":[{"given":"Junjia","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4310-649X","authenticated-orcid":false,"given":"Fanyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyue","family":"Ou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunli","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3545-8866","authenticated-orcid":false,"given":"Yian","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Stomatology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianman","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiqun","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral &amp; Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of Education Hubei Key Laboratory of Stomatology School &amp; Hospital of Stomatology Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7077-9863","authenticated-orcid":false,"given":"Xiaoxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"School &amp; Hospital of Stomatology Wuhan University  Wuhan P. 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