Modulating Schwann cell reprogramming with biomaterials: targeting signaling networks for peripheral nerve regeneration

Peripheral nerve regeneration relies critically upon the remarkable plasticity of Schwann cells (SCs), which undergo profound phenotypic reprogramming after injury to execute myelin clearance, neurotrophic support, axonal guidance, and target reinnervation. This reprogramming is governed by a dynamic interplay of signaling networks—including c-Jun, Notch, neuregulin 1 (NRG1)/ErbB receptor tyrosine kinase, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR), transforming growth factor-β (TGF-β)/Smad, Wnt/β-catenin, integrin–focal adhesion kinase (FAK) and Hippo–Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)—that collectively regulate SC dedifferentiation, migration, proliferation, and remyelination. Here, we summarize how these pathways integrate biochemical and mechanical cues from the injury microenvironment to determine SC fate and function. Building on the mechanistic foundation, we highlight emerging biomaterial-based strategies, particularly advanced nerve guidance conduits and functionalized scaffolds, that are being explored to modulate these signaling networks and thereby influence SC reprogramming and neural regeneration. Although such approaches have been shown promise in preclinical models, current evidence remains largely experimental; whether biomaterials can steer SC behavior in spatiotemporally defined manner and overcome the limitations of current clinical approaches has yet to be established. We propose that therapeutic strategies centered on multi-signal, biomaterial-mediated regulations of SC plasticity represent a promising direction for peripheral nerve repair. Finally, we discuss key challenges and future opportunities in translating these findings into clinical practice, emphasizing the need for microenvironment-responsive platforms that recapitulate the natural dynamics of successful nerve regeneration.