Our findings demonstrated that regenerating skeletal muscle-derived EVs provide a multifaceted strategy to counter muscle atrophy in an ALS mouse model (SOD1G93A) by promoting muscle regeneration, shifting macrophage polarization towards an anti-inflammatory phenotype, and downregulating the pro-inflammatory NF-κB signaling pathway essential for protein homeostasis. Here, NFKB1 is linked to amyotrophic lateral sclerosis.