Multifunctional PDGF Nanofiber and MnCe Nanozyme-Incorporated Composite Hydrogel for Enhanced Skeletal Muscle Regeneration.

Volumetric muscle loss (VML) results in sustained functional impairment owing to inadequate endogenous muscle regeneration. Herein, we report a multifunctional, injectable and adhesive hydrogel designed to synergistically enhance myogenic regeneration and reconstruct a pro-regenerative microenvironment for VML repair. The GelMA hydrogel integrates platelet-derived growth factor-mimetic supramolecular nanofibers (PDGF-NF) and a cerium-manganese nanozyme (MnCe). The PDGF-NF recapitulate endogenous myokine signaling, thereby promoting myoblast proliferation and myogenic differentiation, while overcoming the intrinsic limitations of recombinant growth factors. Concurrently, the MnCe nanozyme efficiently scavenges excessive reactive oxygen species and modulates macrophage polarization from the pro-inflammatory M1 phenotype toward the pro-regenerative M2 phenotype, collectively alleviating oxidative stress, chronic inflammation at the defect site. As a result, the composite hydrogel establishes a favorable microenvironment that supports angiogenesis and muscle tissue remodeling. In a VML animal model, the MnCe-PDGF@GM hydrogel enhanced myofiber regeneration by 181.5%, and reduced fibrotic deposition by 55.8%, resulting in markedly improved functional recovery at 4 weeks. This work highlights a biomimetic and microenvironment-adaptive strategy that integrates myokine-mimicking nanofibers and multifunctional nanozymes, offering a promising therapeutic platform for effective VML regeneration.