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Background: Muscle disuse and offloading in microgravity are likely the primary factors mediating spaceflight-induced muscle atrophy, for which there is currently no effective treatment other than exercise. Extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) possess anti-inflammatory and antioxidant properties, offering a potential strategy for combating weightless muscular atrophy. Methods: In this study, human BMSCs-EVs (hBMSC-EVs) were isolated using super-centrifugation and characterized. C2C12 myotube nutrition-deprivation and mice tail suspension models were established. Subsequently, the diameter of C2C12 myotubes, Soleus mass, cross-sectional area (CSA) of muscle fibers, and grip strength in mice were assessed to investigate the impact of hBMSC-EVs on muscle atrophy. Immunostaining, transmission electron microscopy observation, and western blot analysis were employed to assess the impact of hBMSC-EVs on muscle fiber types, ROS levels, inflammation, ubiquitin–proteasome system activity, and autophagy lysosome pathway activation in skeletal muscle atrophy. Results: The active hBMSC-EVs can be internalized by C2C12 myotubes and skeletal muscle. hBMSC-EVs can effectively reduce C2C12 myotube atrophy caused by nutritional deprivation, with a concentration of 10 × 108 particles/mL showing the best effect (P < 0.001). Additionally, hBMSC-EVs can down-regulate the protein levels associated with UPS and oxidative stress. Moreover, intravenous administration of hBMSC-EVs at a concentration of 1 × 1010 particles/mL can effectively reverse the reduction in soleus mass (P < 0.001), CSA (P < 0.01), and grip strength (P < 0.001) in mice caused by weightlessness. They demonstrate the ability to inhibit protein degradation mediated by UPS and autophagy lysosome pathway, along with the suppression of oxidative stress and inflammatory responses. Furthermore, hBMSC-EVs impede the transition of slow muscle fibers to fast muscle fibers via upregulation of Sirt1 and PGC-1α protein levels. Conclusions: Our findings indicate that hBMSC-EVs are capable of inhibiting excessive activation of the UPS and autophagy lysosome pathway, suppressing oxidative stress and inflammatory response, reversing muscle fiber type transformation, effectively delaying hindlimb unloading-induced muscle atrophy and enhancing muscle function. Our study has further advanced the understanding of the molecular mechanism underlying muscle atrophy in weightlessness and has demonstrated the protective effect of hBMSC-EVs on muscle atrophy. [ABSTRACT FROM AUTHOR]