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

Vollständiger Abstract

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ABSTRACT 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.