Targeting CD300a Signaling With a Phosphatidylserine‐Presenting Hydrogel Rescues Macrophage Dysfunction and Accelerates Diabetic Wound Healing
- 1Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology Nanjing University Nanjing China
- 2Department of Stomatology Qilu Hospital (Qingdao) Cheeloo College of Medicine Shandong University Qingdao China
Abstract
The delayed healing of diabetic wounds involves both impaired efferocytosis and dysfunctional phosphatidylserine (PS) receptor signaling, leading to macrophage defects in migration, persistent M1 polarization, and diminished cellular resilience. To address this multifaceted pathology, a bioactive wound dressing was developed by incorporating PEGylated RGD‐grafted phosphatidylserine liposomes (PEG/RGD‐PSLs) into a photocrosslinkable hyaluronic acid methacryloyl (HAMA) hydrogel matrix. This platform provides sustained, delivery of a biomimetic “eat‐me” signal while actively reprogramming macrophage behavior. Under diabetic‐mimicking stress conditions, PEG/RGD‐PSLs significantly enhanced macrophage migration, promoted M1‐to‐M2 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‐κB pathway and downregulated pro‐inflammatory genes. Critically, siRNA‐mediated CD300a knockdown abolished these anti‐inflammatory and NF‐κB‐suppressive 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‐reparative M2‐dominant state. Collectively, this study identifies the PS/CD300a/NF‐κB axis as a key regulatory node for rescuing macrophage dysfunction and establishes a functionally active hydrogel‐based therapy for chronic diabetic wounds.
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BibTeX
@article{wu2026targeting,
title = {{Targeting CD300a Signaling With a Phosphatidylserine‐Presenting Hydrogel Rescues Macrophage Dysfunction and Accelerates Diabetic Wound Healing}},
author = {Lele Wu and Xuetong Hao and Yang Zou and Xinglin Chen and Junyan Kong and Chunning Gu and Wenjie Ma and Zhongjun Yang and Huifen Liu and Mengmeng Liu and Xin Tong},
journal = {Advanced Healthcare Materials},
year = {2026},
month = aug,
doi = {10.1002/adhm.71648},
url = {https://doi.org/10.1002/adhm.71648},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting CD300a Signaling With a Phosphatidylserine‐Presenting Hydrogel Rescues Macrophage Dysfunction and Accelerates Diabetic Wound Healing
AU - Lele Wu
AU - Xuetong Hao
AU - Yang Zou
AU - Xinglin Chen
AU - Junyan Kong
AU - Chunning Gu
AU - Wenjie Ma
AU - Zhongjun Yang
AU - Huifen Liu
AU - Mengmeng Liu
AU - Xin Tong
PY - 2026
DA - 2026/08/30
JO - Advanced Healthcare Materials
DO - 10.1002/adhm.71648
UR - https://doi.org/10.1002/adhm.71648
AB - The delayed healing of diabetic wounds involves both impaired efferocytosis and dysfunctional phosphatidylserine (PS) receptor signaling, leading to macrophage defects in migration, persistent M1 polarization, and diminished cellular resilience. To address this multifaceted pathology, a bioactive wound dressing was developed by incorporating PEGylated RGD‐grafted phosphatidylserine liposomes (PEG/RGD‐PSLs) into a photocrosslinkable hyaluronic acid methacryloyl (HAMA) hydrogel matrix. This platform provides sustained, delivery of a biomimetic “eat‐me” signal while actively reprogramming macrophage behavior. Under diabetic‐mimicking stress conditions, PEG/RGD‐PSLs significantly enhanced macrophage migration, promoted M1‐to‐M2 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‐κB pathway and downregulated pro‐inflammatory genes. Critically, siRNA‐mediated CD300a knockdown abolished these anti‐inflammatory and NF‐κB‐suppressive 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‐reparative M2‐dominant state. Collectively, this study identifies the PS/CD300a/NF‐κB axis as a key regulatory node for rescuing macrophage dysfunction and establishes a functionally active hydrogel‐based therapy for chronic diabetic wounds.
SN - 2192-2640
SN - 2192-2659
ER -