Chiral Hydrogel Nerve Conduit Boosts Peripheral Nerve Regeneration via Regulation of Schwann Cell Reprogramming

The Schwann cell (SC) is essential in peripheral nerve regeneration by reprogramming into a stem-like "repair Schwann cell" (rSC) phenotype; however, maintaining the rSC stemness remains an unmet challenge. Chirality is a fundamental factor controlling cell fate, and its potential role in regulation of SC reprogramming has long been ignored and remains poorly understood. Herein, inspired by natural chiral components in the SC microenvironment, chiral hydrogel nerve conduits are prepared by supramolecular assembly of l/d-phenylalanine derivatives (l/d-Phe) in polymeric chitosan-gelatin conduits. Right-handed l-Phe fibers within hydrogel conduits maintain the stemness of rSC through enhanced stereoselective interaction between collagen IV and l-Phe fibers triggered by collagen IV-Integrin alpha 1 beta 1, MAPK, and YAP/TAZ signaling pathways and finally activate the key regulator of SC reprogramming, the c-Jun pathway. In the rat model of a sciatic nerve defect, the l-Phe hydrogel nerve conduit significantly enhances nerve regeneration, exhibiting markedly improved histological, electrophysiological, and functional outcomes. The findings reveal the chirality-dependent regulation of SC reprogramming in a pioneering way, offering potential strategies for nerve regeneration therapies.