Lin Gan, Tongtong Xu, Dandan Zheng, Ning Zhu, Sijia Li, Shiyu Deng, Qianyuan Lian, Jixian Wang, Wanlu Li, Zhijun Zhang, Guo‐Yuan Yang, Wenguo Cui, Yaohui Tang, Huitong Ruan
ABSTRACT The vascular hyperinflammatory microenvironment significantly influences the regeneration and repair of central nervous system (CNS) following injury. Training immune behavior of immune cells under stress conditions is crucial for maintaining vascular microenvironment homeostasis and restoring vascular function. In this study, we engineer a novel hyperinflammatory regulatory peptide (mND13) by rational grafting of a DJ‐1‐derived peptide with an MMP‐2 responsive peptide motif. This modified peptide is further conjugated onto hyaluronic acid methacrylate (HAMA) microspheres via photo‐click chemistry and microfluidic technology, generating mND13@HAMA microspheres. This platform induces microglia immuno‐training, inhibits their pro‐inflammatory polarization, thus orchestrating neurovascular niche remodeling and promoting neural recovery through immune‐vascular crosstalk. Both in vitro and in vivo investigations show that these immune‐functionalized peptide microspheres mND13@HAMA drastically decrease endothelial cell apoptosis and the expression of pro‐inflammatory molecules like iNOS, CD86 and IL‐1β in microglia. To further enhance post‐stroke angiogenesis, we co‐deliver VEGF liposomes with mND13@HAMA, which is proven to promote vascular sprouting and growth while inhibiting vascular apoptosis. This combined system markedly reduces brain atrophy volume in stroke mouse, improves neurobehavioral functions, and enhances angiogenesis. In conclusion, this immunomodulatory microsphere, capable of training immune cell behavior, holds significant therapeutic value for treating stroke along with other CNS injuries.