Hierarchically Injectable Hydrogel Sequentially Delivers AntagomiR‐467a‐3p‐Loaded and AntagomiR‐874‐5p‐Loaded Satellite‐Cell‐Targeting Bioengineered Extracellular Vesicles Attenuating Sarcopenia

Abstract

Sarcopenia is a geriatric disease characterized by reduced muscle function and mass. The capacity to self-renew and myogenesis of satellite cells (SCs) declines with age, resulting in age-related sarcopenia. MicroRNAs (miRNAs) can regulate the proliferation and myogenesis of SCs. In this study, it is identified that miR-467a-3p and miR-874-5p could respectively mediate the stemness and myogenesis of SCs by performing bioinformatics analysis. AntagomiR-467a-3p (ant-467a) and antagomiR-874-5p (ant-874) improve the stemness and myogenesis of SCs, respectively. SC-targeting extracellular vesicles (EVs) are constructed by overexpressing TSG101 on the surface of EVs isolated from bone marrow mesenchymal stem cells. Ant-467a loaded EVs (EVs-467a) and ant-874 loaded EVs (EVs-874) are prepared by transferring ant-467a and ant-874 into SC-targeting EVs. EVs-467a and EVs-874 are more effective than ant-467a and ant-874 in promoting the stemness and myogenesis of SCs. Sequentially intermuscular injection of EVs-467a and EVs-874 significantly improve sarcopenia in ovariectomy mice. The effects of multiple injections of EVs-467a and EVs-874 in the treatment of sarcopenia could be achieved by using a hierarchically injectable hydrogel to sustainedly release EVs-467a and EVs-874 in vivo. The findings provide an EV-based SC-targeting antagomiRNAs controlled release strategy as a novel therapy against sarcopenia.

Beyond Traditional Medicine: EVs-Loaded Hydrogels as a Game Changer in Disease Therapeutics

“…Some miRNAs, such as miR-1 [ 171 ] and miR-133 [ 172 ], have been shown to play an important role in promoting muscle regeneration, while other miRNAs are pathogenic to muscle wasting, such as miR-29b [ 173 ] and miR-628 [ 174 ]. Xu et al [ 175 ] showed that miR-467a-3p and miR-874-5p inhibited the differentiation of SCs and the formation of muscle tissue, respectively. They overexpressed TSG101 to target SCs on the BMSCs-EVs surface, and transported antagomiR-467a-3p and antagomiR-874-5p, respectively, to construct two engineered EVs.…”