Injectable multifunctional quaternized carboxymethyl chitosan-hyaluronic acid hydrogel loaded with exosomes from microglia overexpressing miR-124-3p for the treatment of traumatic brain injury.

Traumatic brain injury (TBI) continues to be a significant worldwide health issue because of the blood-brain barrier's restrictive properties and the limited distribution of therapeutic agents, highlighting the necessity for brain-compatible biomaterials capable of attenuating neuroinflammation and supporting neural recovery. In this work, we developed a multifunctional injectable hydrogel (QCC/OHM@ExosmiR-124) incorporating microglia-derived exosomes enriched with miR-124-3p to modulate post-injury inflammation through inhibition of the mTOR signaling pathway. The hydrogel, formulated from quaternized carboxymethyl chitosan (QCC) and oxidized methacrylated hyaluronic acid (OHM), exhibited excellent biocompatibility, injectability, antibacterial activity, and mechanical compliance with brain tissue. In vitro, QCC/OHM@ExosmiR-124 suppressed proinflammatory cytokine expression and aided the shift of microglia from the M1 phenotype to the M2 phenotype. In vivo, using a mouse model with controlled cortical impact (CCI), treatment markedly improved neurological performance, including locomotor coordination and both short- and long-term memory. Histological and immunofluorescence analyses further revealed reduced neuroinflammatory responses and enhanced neuronal survival. Collectively, these findings suggest that QCC/OHM@ExosmiR-124 serves as a promising biomaterial platform for TBI therapy by establishing a neuroprotective microenvironment and regulating inflammatory signaling. Future studies will aim to refine exosome delivery and evaluate translational feasibility.