Multi-omics profiling of a self-assembling bioactive hydrogel for immunomodulation and myogenesis in volumetric muscle loss

Skeletal muscle inherently possesses regenerative capabilities, but recovery from severe volumetric muscle loss (VML) is often constrained, potentially resulting in loss of muscular functionality. Effective biomaterial interventions are rare. To address these gaps, we developed a novel injectable hydrogel, SiCP@InjGel, which utilizes in situ self-assembly to combine puerarin, chitosan, and mesoporous silica nanoparticles, targeting skeletal muscle repair. This hydrogel was rigorously tested in mice, rat, and porcine VML models through in vitro and in vivo experiments, demonstrating its ability to modulate the immune microenvironment, enhance myogenesis, and improve functional muscle recovery. Utilizing multiple state-of-the-art omics technologies, including mass cytometry and single-cell RNA sequencing, we identified that it increased Pdpn+ macrophages and MyoG+ muscle stem cells, reshaping the immune landscape and accelerating muscle regeneration at molecular and cellular resolutions. These findings establish SiCP@InjGel as a multifunctional biomaterial platform with significant translational potential for clinical management of severe skeletal muscle injuries.