A Microenvironment-Adaptive Scaffold Rejuvenates Peripheral Nerve Regeneration During Aging Via Dual Modulation of Ferroptotic Stimuli in Schwann Cells.

Repairing peripheral nerve injury remains a clinical challenge due to its limited regenerative capacity and the situation is further compounded with age. In this study, we identified the dysregulated repair program of Schwann cells (SCs) as a key feature of the aging-dependent impairment of nerve regeneration, mediated by dual influence of ferroptosis. The ferroptosis-stressor-rich microenvironment inhibits SC function in regenerating nerves. Moreover, the persistent intracellular ferroptosis stressor accumulation could accentuate senescence-associated secretory phenotype (SASP) expression in SCs, culminating in the disruption of redifferentiation trajectory and repair programs of SCs. Herein, a composite nerve conduit integrating microenvironment-responsive Ga-PTA nanoparticles and maxillofacial-derived mesenchymal stem cells (Mmscs) is developed by melt electrospinning writing (MEW). Mechanistically, Ga-PTA nanoparticles competitively inhibited excessive ferroptosis to establish a pro-regenerative niche. Meanwhile, Mmscs was induced to differentiate into SC-like cells which bypassed the redifferentiation impairment of resident SASP-expressing SCs, offering promising therapeutic strategies for peripheral nerve and other tissue injuries during aging.