Silencing Myostatin Using In Vivo Self-Assembled siRNA Protects Against Cancer- and Dexamethasone-Induced Muscle Atrophy.

Abstract

Maintaining skeletal muscle mass is crucial for health, as muscle atrophy caused by drugs, cancer, or aging poses serious risks. However, there are few effective pharmacological interventions targeting muscle atrophy, highlighting the need for new therapeutic strategies. In this study, in vivo self-assembled siRNA is designed to silence myostatin (MSTN), a key regulator of muscle growth and atrophy, aiming to prevent muscle atrophy. Using synthetic constructs and the host liver as a scaffold, the assembly of MSTN-siRNA is guided into muscle-specific peptide MSP-tagged small extracellular vesicles (sEVs). These MSP-tagged sEVs selectively deliver MSTN-siRNA to muscle tissue. Treatment significantly reduces MSTN protein levels in skeletal muscle, promotes muscle mass gain in healthy mice, and protectes skeletal muscles from atrophy in cancer- and dexamethasone-induced muscle atrophy models. Notably, the sEV-encapsulated MSTN-siRNA is produced in a nontoxic, nonimmunogenic, and biocompatible manner. This study offers a promising therapeutic approach for muscle atrophy, addressing a key gap in current treatment options and potentially improving outcomes for patients with muscle-wasting conditions.