Hierarchically Injectable Hydrogel Sequentially Delivers AntagomiR‐467a‐3p‐Loaded and AntagomiR‐874‐5p‐Loaded Satellite‐Cell‐Targeting Bioengineered Extracellular Vesicles Attenuating Sarcopenia
Hanhao Dai, Jun Luo, Lili Deng, Chao Song, Zhibo Deng, Yijing Wu, Song Gu, Jie Xu
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.