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Here, this work reports engineered macrophage\u2010derived exosomes overexpressing GNA12 and GNA13 (G12G13MExos) that reprogram macrophages toward the M2c anti\u2010inflammatory phenotype and astrocytes into a neuroprotective phenotype. G12G13MExos enhance astrocyte\u2010mediated clearance of myelin debris, glutamate homeostasis, and synapse formation while fostering astrocyte\u2010neuron crosstalk. These effects improve neuronal survival and drove neural stem cell differentiation into V2a neurons, facilitating neural circuit reconstruction. This work develops a chitosan\u2010based thermosensitive hydrogel that functions as a \u201cnasal exosome intelligent slow\u2010release depot\u201d to enable efficient and targeted exosome delivery. This delivery system bypasses hepatic and renal sequestration and overcomes the blood\u2010spinal cord barrier, significantly enhancing therapeutic efficacy. This strategy integrates engineered exosomes with a responsive delivery platform, modulating the inflammatory microenvironment, enhancing cellular crosstalk, and promoting neural repair. This comprehensive approach offers a promising translational avenue for SCI treatment and other central nervous system disorders.<\/jats:p>","DOI":"10.1002\/advs.202504486","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T09:00:05Z","timestamp":1750410005000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Nasal Delivery of Engineered Exosomes via a Thermo\u2010Sensitive Hydrogel Depot Reprograms Glial Cells for Spinal Cord Repair"],"prefix":"10.1002","volume":"12","author":[{"given":"Yangyang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, The First Affiliated Hospital of Harbin Medical University Harbin Medical University  Harbin 150000 P. R. 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