ABSTRACT Skeletal muscle possesses a remarkable ability to repair and regenerate following moderately severe injuries (e.g., tears, sprains, etc.). However, following a substantial loss of muscle tissue (>20%), termed as a volumetric muscle loss (VML), the muscle tissue is unable to repair and regenerate itself. VML injuries show persistent inflammation and fibrosis at the injury site. Currently, there is no definitive therapy for VML that regenerates or restores the extensive loss of muscle mass. Our previous work revealed a correlation between impaired regeneration and a dysregulated immune response in VML. This proposal will integrate regenerative and immunomodulatory strategies to boost muscle recovery post-VML. The proposed regenerative therapy is a biomimetic sponge-like scaffold composed of extracellular matrix (ECM) proteins. In a rodent model of VML, implantation of this scaffold significantly enhanced muscle structure and function. This work will modify the scaffold design to achieve sustained release of an FDA-approved immunosuppressant drug called FK-506 (Aim 1). Sustained release of FK-506 is expected to modulate the intense and chronic inflammatory response to VML and improve regenerative outcomes. Our second approach for VML repair aims to engage and modulate helper T cells. The function of these cells is primarily mediated through their secreted products. We will identify specific helper T cell subsets that can promote muscle regeneration. Helper T cell-derived pro-regenerative secretory products will then be locally delivered to the VML injury site using biomimetic sponges to drive muscle regeneration (Aim 2). We will perform a thorough histological, gene & protein expression, and flow cytometry analysis coupled with peak torque measurement, in both aims to provide mechanistic insight into each therapy. The proposed plan will provide research training and exposure to both undergraduate and graduate students, making them more competitive for academic and industry positions.