Age-related skeletal muscle aging can lead to sarcopenia and is closely associated with cellular senescence and mitochondrial dysfunction. Neonatal mammalian muscle exhibits a strong regenerative capacity, and neonatal muscle extracellular vesicles (NMEVs) show therapeutic potential against skeletal muscle aging. In this study, we isolated NMEVs for the first time and found that they significantly alleviated palmitic acid (PA)-induced senescence, mitochondrial dysfunction, and lipid accumulation in C2C12 cells. in vivo , we developed a bilayer microneedle (MN) system loaded with NMEVs (NMEVs@PLGA@Fucoidan-HA MN) and applied it to aged mice. The MN effectively enhanced mitochondrial function, reduced muscle aging and fibrosis, and decreased lipid deposition. Mechanistically, miR-542-3p enriched in NMEVs directly targeted and downregulated Asxl2-PPARγ, leading to reduced lipid accumulation. At the same time, it suppressed Eef1a1 to activate the AMPK pathway, thereby improving mitochondrial function and attenuating cellular senescence. Our findings demonstrate the protective role of NMEVs delivered via an innovative MN system against muscle aging, where miR-542-3p plays a central role by concurrently targeting Eef1a1 and Asxl2 to mitigate senescence and lipid dysregulation. This study reveals a novel molecular mechanism underlying the anti-aging potential of NMEVs and offers a promising therapeutic strategy for skeletal muscle aging.
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