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While current treatment options, primarily surgery and medication, vary with TBI severity, there is no universal therapeutic agent applicable in both surgical and medical contexts. In the present study, exosomes derived from induced neural stem cells (iNSC\u2010Exo) as a versatile therapeutic agent for TBI are investigated using a preclinical murine model. The iNSC\u2010Exo treatment is found to exert therapeutic effects by mediating anti\u2010neuroinflammation and neuroprotection, thereby promoting functional and cognitive recovery in TBI mice. Besides, two clinically inspired administration modalities are established for iNSC\u2010Exo: local delivery and systemic delivery. Their efficacy is enhanced via a novel injectable hydrogel and RVG targeting for systemic delivery, respectively. Finally, the unprecedented single\u2010cell characterization of mouse brain tissue, both pre\u2010 and post\u2010iNSC\u2010Exo treatment, confirms that microglia represent the predominant type of cells affected. Two microglial subpopulations (i.e., Microglia_Nrg3 and Microglia_Rarb) are identified with a reduced state of differentiation, and their connectivity with neurons is predicted through activation of the NRXN signaling pathway. Overall, these findings demonstrated that iNSC\u2010Exo offers a versatile and potent treatment platform with clinical potential for TBI management.<\/jats:p>","DOI":"10.1002\/advs.202508574","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T09:25:21Z","timestamp":1758705921000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Clinically Inspired Multimodal Treatment Using Induced Neural Stem Cells\u2010Derived Exosomes Promotes Recovery of Traumatic Brain Injury through Microglial Modulation"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8675-2652","authenticated-orcid":false,"given":"Jiaojiao","family":"Li","sequence":"first","affiliation":[{"name":"Department of ORL\u2010HNS Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine Shanghai 200434 China"},{"name":"Plasma Medicine and Surgical Implants Center 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