Myomerger-derived peptide enhances skeletal muscle tropism and reduces liver transduction of lipid nanoparticles for gene delivery

Lipid nanoparticles (LNPs) are emerging as nonviral vectors for gene therapy; yet, their strong liver tropism and lack of tissue specificity remain limiting. Here, we developed, through rational design, a skeletal muscle-targeted delivery platform by functionalizing LNPs with MyomP1, an extracellular conserved peptide derived from the muscle-specific fusogenic protein Myomerger. MyomP1-LNPs were engineered to encapsulate plasmid DNA or mRNA. <i>In vitro</i>, MyomP1 conjugation significantly increased transduction efficiency in murine and human myoblasts and myotubes. <i>In vivo</i>, MyomP1-LNPs significantly enhanced muscle transduction when delivering DNA cargo, strongly reduced liver accumulation following intramuscular and intravenous mRNA delivery, and attenuated local immune activation. This work demonstrates a ligand-guided strategy to overcome organ-specific barriers in nonviral gene transfer, with improved safety and specificity. It suggests that MyomP1-engineered LNPs hold strong potential to improve therapeutic outcomes for patients with rare muscle diseases, offering a promising alternative to traditional viral gene therapy platforms.