Harnessing the Paracrine Function of NAMPT to Promote Skeletal Muscle Regeneration

Following tissue injury, a specific subset of macrophages called dwelling macrophages coordinates regeneration by establishing a transient niche and secreting extracellular NAMPT, which activates satellite cells through CCR5 signalling. We focused on NAMPT’s C-terminal fragment (NAMPT422-491), which lacks enzymatic activity but mimics cytokine structure. NAMPT422-491 enhanced muscle regeneration in a murine volumetric muscle loss model. ECM-binding and Fc-fusion variants further improved outcomes by enhancing retention and half-life. Additionally, LNP-encapsulated NAMPT422-491 mRNA promoted regeneration upon local delivery. These findings position NAMPT422-491 as a potent, versatile therapeutic candidate for skeletal muscle regeneration, with broad translational potential across delivery platforms.