Nasal Delivery of Engineered Exosomes via a Thermo-Sensitive Hydrogel Depot Reprograms Glial Cells for Spinal Cord Repair

Abstract

Spinal cord injury (SCI) presents formidable therapeutic challenges due to its multifaceted pathological complexity. Here, this work reports engineered macrophage-derived exosomes overexpressing GNA12 and GNA13 (G12G13MExos) that reprogram macrophages toward the M2c anti-inflammatory phenotype and astrocytes into a neuroprotective phenotype. G12G13MExos enhance astrocyte-mediated clearance of myelin debris, glutamate homeostasis, and synapse formation while fostering astrocyte-neuron crosstalk. These effects improve neuronal survival and drove neural stem cell differentiation into V2a neurons, facilitating neural circuit reconstruction. This work develops a chitosan-based thermosensitive hydrogel that functions as a “nasal exosome intelligent slow-release depot” to enable efficient and targeted exosome delivery. This delivery system bypasses hepatic and renal sequestration and overcomes the blood-spinal 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.