Exercise confers systemic health benefits through inter-organ signaling, yet the precise molecular carriers of these effects remain incompletely defined. Extracellular vesicles (EVs), particularly exosomes released during physical activity (ExEVs), have emerged as stable, targeted vehicles of exerkines. These vesicles transport myokines such as interleukin-6 and irisin, together with microRNAs (including miR-181a-5p, miR-486-5p and miR-342-5p), mitochondrial DNA and metabolites, enabling muscle-to-organ communication that improves insulin sensitivity, dampens inflammation and supports neuronal protection. Both aerobic and resistance exercise markedly elevate EV secretion from skeletal muscle and remodel their cargo profiles. Translational evidence is compelling: administration of ExEVs isolated from trained animals preserves muscle mass and accelerates regeneration in models of disuse atrophy, providing proof-of-concept for exercise-mimetic therapeutics that operate independently of physical activity. Human studies similarly link post-exercise EV signatures to enhanced metabolic function and attenuated markers of biological aging.

Despite these advances, methodological heterogeneity in EV isolation (ultracentrifugation versus size-exclusion chromatography) and uncertainty regarding cellular origin continue to limit progress. We therefore advocate a systematic multi-omics roadmap—integrating transcriptomics, proteomics and lipidomics—applied across exercise modalities, sex-specific responses and age-stratified cohorts. Such an approach would establish the foundation for vesicle-based “exercise pharmacology” capable of delivering concentrated therapeutic payloads for obesity, type 2 diabetes and sarcopenia. Realization of this vision could fundamentally redefine exercise prescription in clinical practice, transforming a lifestyle intervention into a precision molecular therapy.