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To address this multifaceted pathology, a bioactive wound dressing was developed by incorporating PEGylated RGD\u2010grafted phosphatidylserine liposomes (PEG\/RGD\u2010PSLs) into a photocrosslinkable hyaluronic acid methacryloyl (HAMA) hydrogel matrix. This platform provides sustained, delivery of a biomimetic \u201ceat\u2010me\u201d signal while actively reprogramming macrophage behavior. Under diabetic\u2010mimicking stress conditions, PEG\/RGD\u2010PSLs significantly enhanced macrophage migration, promoted M1\u2010to\u2010M2 phenotypic transition, and conferred robust cytoprotection by preserving mitochondrial integrity, attenuating oxidative stress, and suppressing pathological extracellular vesicle release. Mechanistically, PS binding upregulated the inhibitory receptor CD300a, which suppressed the MyD88\/NF\u2010\u03baB pathway and downregulated pro\u2010inflammatory genes. Critically, siRNA\u2010mediated CD300a knockdown abolished these anti\u2010inflammatory and NF\u2010\u03baB\u2010suppressive effects, establishing CD300a as necessary for therapeutic action. In a diabetic rat model, a single application of the bioactive hydrogel significantly accelerated wound closure, stimulated angiogenesis, improved organized collagen deposition, and actively shifted the wound immune microenvironment toward a pro\u2010reparative M2\u2010dominant state. Collectively, this study identifies the PS\/CD300a\/NF\u2010\u03baB axis as a key regulatory node for rescuing macrophage dysfunction and establishes a functionally active hydrogel\u2010based therapy for chronic diabetic wounds.<\/jats:p>","DOI":"10.1002\/adhm.71648","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T03:46:06Z","timestamp":1788147966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting CD300a Signaling With a Phosphatidylserine\u2010Presenting Hydrogel Rescues Macrophage Dysfunction and Accelerates Diabetic Wound Healing"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-0293","authenticated-orcid":false,"given":"Lele","family":"Wu","sequence":"first","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5892-630X","authenticated-orcid":false,"given":"Xuetong","family":"Hao","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zou","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2272-1439","authenticated-orcid":false,"given":"Xinglin","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"Kong","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunning","family":"Gu","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Ma","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Stomatology Qilu Hospital (Qingdao) Cheeloo College of Medicine Shandong University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1329-2041","authenticated-orcid":false,"given":"Huifen","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4580-8735","authenticated-orcid":false,"given":"Mengmeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Stomatology Qilu Hospital (Qingdao) Cheeloo College of Medicine Shandong University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tong","sequence":"additional","affiliation":[{"name":"Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.2694"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009337"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000339613"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(05)67700\u20108"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.1094"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202212300"},{"issue":"6","key":"e_1_2_12_8_1","article-title":"Topical Antimicrobial Agents for Treating Foot Ulcers in People With Diabetes","volume":"6","author":"Dumville J. 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