Myogenic Fusogen‐Engineered Lipid Nanoparticles Enhance mRNA Delivery in Skeletal Muscle

ABSTRACT Lipid nanoparticles (LNPs) have emerged as powerful vehicles for mRNA therapeutics, yet efficient delivery to skeletal muscle remains challenging. Here, we engineer LNPs by integrating Myomaker, a muscle‐specific fusogen, onto their surface to enhance skeletal muscle delivery. Optimized Myomaker‐LNP (Mymk‐LNP) formulations demonstrated high fusogen integration, uniform size, and efficient mRNA encapsulation. Mymk‐LNPs exhibited selective in vitro transfection in differentiating myocytes while minimizing uptake in myoblasts and fibroblasts. Systemic and local administration of Mymk‐LNPs in vivo led to significantly increased mRNA delivery to skeletal muscle, particularly in models with muscles undergoing fusion, such as developing muscles in neonatal mice and chemically injured muscles in adult mice. Furthermore, Mymk‐LNPs mediated efficient Cre mRNA‐mediated DNA recombination in injured skeletal muscle as quantified by activation of a Cre‐dependent tdTomato reporter. These findings highlight the potential of fusogen‐engineered LNPs as a targeted and effective platform for delivery of mRNA therapeutics to muscle.