Mitigating Critical Peripheral Nerve Deficit Therapy with Reactive Oxygen Species/Ca²⁺-Responsive Dynamic Hydrogel-Mediated mRNA Delivery

Critical peripheral nerve deficiencies present as one of the most formidable conundrums in the realm of clinical medicine, frequently culminating in structural degradation and derangement of the neuromuscular apparatus. Engineered extracellular vesicles (EVs) exhibit the potential to ameliorate nerve impairments. However, the advent of Wallerian degeneration (WD), an inexorable phenomenon that ensues post peripheral nerve injury, serves as an insurmountable impediment to the direct therapeutic efficacy of EVs. In this investigation, we have fashioned a dynamic network for the conveyance of PTEN-induced kinase 1 (PINK1) mRNA (E-EV-P@HPCEP) using an adaptive hydrogel with reactive oxygen species (ROS)/Ca 2+ responsive ability as the vehicle, bearing dual-targeted, engineered EVs. This intricate system is to precisely deliver PINK1 to senescent Schwann cells (SCs) while concurrently orchestrating a transformation in the inflammatory-senescent milieu following injury, thereby stymying the progression of WD in peripheral nerve fibers through the stimulation of autophagy within the mitochondria of the injured cells and the maintenance of mitochondrial mass equilibrium. WD, conventionally regarded as an inexorable process, E-EV-P@HPCEP achieved functionalized EV targeting, orchestrating a dual-response dynamic release mechanism via boronate ester bonds and calcium chelation, effectuating an enhancement in the inflammatory-senescent microenvironment, which expedites the therapeutic management of nerve deficiencies and augments the overall reparative outcome.