Silk sericin patches delivering miRNA-29-enriched extracellular vesicles-decorated myoblasts (SPEED) enhances regeneration and functional repair after severe skeletal muscle injury

Abstract

Severe skeletal muscle injuries usually lead to a series of poor recovery issues, such as massive myofibers loss, scar tissue formation, significant muscle function impairment, etc. Here, a silk sericin patch delivering miRNA-29-enriched extracellular vesicles-decorated myoblasts (SPEED) is designed for the rapid regeneration and functional repair after severe skeletal muscle injury. Specifically, miR29-enriched extracellular vesicles (miR29-EVs) are prepared and used to deliver miR29 into primary myoblasts, which promote the myotube formation of myoblasts and increase the expression of myogenic genes while inhibiting the expression of fibrotic genes. Our results indicate that miR29-EVs promote the integration of primary myoblasts and host muscle in a severe mouse tibialis anterior (TA) muscle injury model. Moreover, implantation of SPEED drastically stimulates skeletal muscle regeneration, inhibits fibrosis of injured muscles, and leads to significant improvement of muscle contraction forces and motor ability of mice about 3 weeks after treatment. Subsequently, we further evaluate the transcriptomes of TA muscles and find that SPEED can significantly ameliorate energy metabolism and muscular microenvironment of TA muscles on day 9 after implantation. Additionally, bioinformatic analysis and comprehensive molecular biology studies also reveal that the down-regulation of CDC20-MEF2C signaling axis may participate in the muscle repair process. Together, SPEED may serve as an effective alternative for the rapid repair of severe skeletal muscle injuries in the future.