Clinically Inspired Multimodal Treatment Using Induced Neural Stem Cells‐Derived Exosomes Promotes Recovery of Traumatic Brain Injury through Microglial Modulation

Abstract Traumatic brain injury (TBI) poses serious physical, psychosocial, and economic threats to millions of patients globally each year. 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‐Exo) as a versatile therapeutic agent for TBI are investigated using a preclinical murine model. The iNSC‐Exo treatment is found to exert therapeutic effects by mediating anti‐neuroinflammation and neuroprotection, thereby promoting functional and cognitive recovery in TBI mice. Besides, two clinically inspired administration modalities are established for iNSC‐Exo: 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‐cell characterization of mouse brain tissue, both pre‐ and post‐iNSC‐Exo 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‐Exo offers a versatile and potent treatment platform with clinical potential for TBI management.