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Although microneedles (MNs) represent an effective transdermal drug delivery system for acne treatment, the therapeutic effects on the restoration of dysregulated lipid metabolism and the prevention of atrophic acne scars are still lacking. Herein, we develop proteoglycan\u2010mimetic comb polymer (HMC)\u2010based dissolving microneedles (HMC\u2010PEP MNs) with encapsulation of therapeutic peptides. This system effectively targets the acne pathophysiological pathways involving bacterial colonization, lipid dysregulation, chronic inflammation and impaired tissue repair. Specifically, HMC enables sustained release of antimicrobial and anti\u2010inflammatory peptides via multiple non\u2010covalent interactions. HMC\u2010PEP MNs display significant efficacy\n                    <jats:italic>via<\/jats:italic>\n                    eradicating\u00a0\n                    <jats:italic>Cutibacterium acnes<\/jats:italic>\n                    infection, suppressing pro\u2010inflammatory mediator expression, and reducing the TREM2\/M2 macrophage ratio. Integrated transcriptomic and metabolomic analysis reveals that HMC\u2010PEP MNs effectively regulate cholesterol and linoleic acid metabolism, inhibit pro\u2010inflammatory signaling transduction, and reduce keratinocyte proliferation and differentiation by inhibiting the IGF1\/IGF1R\/PI3K\/AKT\/mTOR signaling pathway. Interestingly, HMC\u2010PEP MNs also promote collagen synthesis and ameliorate fibroblast dysfunction, thereby preventing the formation of post\u2010acne dermal atrophy. This study presents an effective therapeutic strategy for acne and elucidates the underlying mechanisms of HMC\u2010PEP MNs, demonstrating considerable promise for clinical translation.\n                  <\/jats:p>","DOI":"10.1002\/smll.202512378","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T11:48:38Z","timestamp":1773143318000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Proteoglycan Mimetics\u2010Based Antimicrobial and Anti\u2010Inflammatory Microneedles Restoring Dysregulated Lipid Metabolism and Suppressing Skin Atrophy for Acne Treatment"],"prefix":"10.1002","volume":"22","author":[{"given":"Kehan","family":"Du","sequence":"first","affiliation":[{"name":"Hubei Engineering Research Center For Biomaterials and Medical Protective Materials School of Chemistry and Chemical Engineering Huazhong University of Science and Technology (HUST)  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo\u2010Ran","family":"Yang","sequence":"additional","affiliation":[{"name":"Hubei Engineering Research Center For Biomaterials and Medical Protective Materials School of Chemistry and Chemical Engineering Huazhong University of Science and Technology (HUST)  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Qi","sequence":"additional","affiliation":[{"name":"Sinopec (Beijing) Research Institute of Chemical Industry Co., Ltd  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Hou","sequence":"additional","affiliation":[{"name":"Sinopec (Beijing) Research Institute of Chemical Industry Co., Ltd  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huinan","family":"Suo","sequence":"additional","affiliation":[{"name":"Department of Dermatology Union Hospital Tongji Medical College HUST  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Qu","sequence":"additional","affiliation":[{"name":"Hubei Engineering Research Center For Biomaterials and Medical Protective Materials School of Chemistry and Chemical Engineering Huazhong University of Science and Technology (HUST)  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Hubei Engineering Research Center For Biomaterials and Medical Protective Materials School of Chemistry and Chemical Engineering Huazhong University of Science and Technology (HUST)  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing\u2010Wen","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Radiology Xijing Hospital Air Force Medical University (AFMU)  Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"Cosme Biotechnology Co., Ltd.  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