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

Area of Science:

• Biomedical Engineering
• Molecular Biology
• Regenerative Medicine

Background:

• Skeletal muscle mass is vital for health, but muscle atrophy from aging, cancer, or drugs presents significant risks.
• Current pharmacological treatments for muscle atrophy are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

• To develop and evaluate an in vivo self-assembled small interfering RNA (siRNA) therapy targeting myostatin (MSTN) to prevent muscle atrophy.
• To investigate the efficacy of MSTN-siRNA delivered via muscle-specific peptide (MSP)-tagged small extracellular vesicles (sEVs) in promoting muscle mass and preventing atrophy.

Main Methods:

• Designed in vivo self-assembled MSTN-siRNA constructs utilizing the liver as a scaffold for assembly.
• Engineered MSP-tagged sEVs for selective delivery of MSTN-siRNA to muscle tissue.
• Evaluated the therapeutic effects in healthy mice and models of cancer- and dexamethasone-induced muscle atrophy.

Main Results:

• Successfully reduced MSTN protein levels in skeletal muscle.
• Demonstrated promotion of muscle mass gain in healthy mice.
• Protected skeletal muscles against atrophy in induced models, with sEV-encapsulated MSTN-siRNA proving nontoxic, nonimmunogenic, and biocompatible.

Conclusions:

• In vivo self-assembled MSTN-siRNA delivered by MSP-tagged sEVs represents a promising therapeutic strategy for muscle atrophy.
• This approach addresses a critical unmet need in treating muscle-wasting conditions.
• The therapy shows potential for improving patient outcomes in various catabolic states.