Secreted protein acidic and rich in cysteine-guided biomimetic delivery of nano-antioxidants reverses muscle atrophy in a mouse model of sarcopenia.

Sarcopenia is currently classified as an unmet medical need with an increasing incidence because of population aging. Excessive reactive oxygen species (ROS) production plays a critical role in the pathogenesis of muscle atrophy, a key feature of sarcopenia, whereas edaravone has been identified as a potent ROS scavenger in screening assays using C2C12 myocytes. In this study, we established an injured muscle-targeted drug delivery system (imDDS), which mimics the secreted protein acidic and rich in cysteine (SPARC)-mediated albumin uptake pathway, to deliver edaravone to damaged muscle tissue. SPARC on the cell surface facilitated the cellular uptake of human serum albumin (HSA) by forming disulfide bonds with the surface or intramolecular thiol groups of HSA. Endogenous albumin labeled with Evans blue accumulated in the injured muscle tissue of mice with sarcopenia, suggesting the potential of albumin to target damaged muscle tissue. Thiol-rich, edaravone-loaded HSA nanoparticles were internalized into hydrogen peroxide-injured myocytes in a SPARC-dependent manner, and edaravone was released into the cytosol in response to the acidic endosomal environment, resulting in a significant reduction of intracellular ROS levels. The nanoparticles also preferentially accumulated in SPARC-positive cells within the damaged muscle tissue of mice with sarcopenia and attenuated oxidative stress, thereby significantly restoring skeletal muscle mass and endurance. These findings suggest that edaravone-based, SPARC-guided biomimetic delivery represents a promising therapeutic strategy for sarcopenia and other muscle-related disorders.