Irisin-Loaded Physically Cross-linked Silk Fibroin Hydrogel Promotes Muscle Fiber Regeneration in Volumetric Muscle Loss

Volumetric muscle loss (VML), often resulting in irreversible motor impairment, poses a significant challenge for musculoskeletal repair. This study introduces a biodegradable silk fibroin (SF) hydrogel as an irisin delivery system for VML treatment. With controlled <i>in vivo</i> degradation (4-6 weeks), the hydrogel synchronizes irisin release with muscle regeneration. Irisin-loaded SF hydrogels enhance muscle fiber maturation, alignment, and the cross-sectional area (CSA). Mechanistically, irisin promotes myogenic differentiation by activating satellite cells and aiding neuromuscular junction reconstruction. It also induces macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype and stimulates the secretion of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), enhancing inflammation resolution and muscle regeneration. This study is the first to demonstrate that an irisin delivery strategy using a biodegradable SF hydrogel effectively enhances VML repair by modulating both myogenic regeneration and the immune microenvironment, offering a promising therapeutic approach for clinical applications.