A dual-release system synergizing inflammation regulation and pro-angiogenesis for the treatment of spinal cord injury.

Following spinal cord injury (SCI), excessive inflammatory responses induce severe secondary neural damage, while insufficient vascular reconstruction limits nutrient supply and tissue regeneration, collectively hindering neurological functional recovery. Therefore, the development of temporally coordinated therapeutic strategies that align with the pathological progression of SCI is of great importance. In this study, using a solid-in-oil-in-water (S/O/W) emulsification method, we constructed a dual-release microsphere system by incorporating hypoxia-preconditioned mesenchymal stem cell-derived nanovesicles (hypo-NV) within alginate microcapsules and subsequently co-loading them with methylprednisolone (MP) into poly(lactic-co-glycolic acid) (PLGA) microspheres (NV-Alg@MP-PLGA), enabling the programmed delivery of both therapeutic agents. During the early stage after injury, MP was rapidly released to suppress excessive inflammation and alleviate secondary damage. Meanwhile, the alginate microcapsules mediated the sustained release of hypo-NV to provide continuous support for angiogenesis and improvement of the regenerative microenvironment during the subsequent regenerative phase. Both in vitro and in vivo studies demonstrated that this dual-release system achieved the sequential delivery of MP and hypo-NV, thereby promoting vascular regeneration, neuronal survival, and axonal regeneration, which ultimately resulted in improved tissue repair and locomotor functional recovery following SCI. Collectively, this strategy represents a promising therapeutic approach with substantial translational potential for the spatiotemporal treatment of SCI.