Exercise-derived extracellular vesicles in oncology: a new frontier for translational nanomedicine

Fig. 1. Engineered extracellular vesicles (EVs) in oncology. Schematic representation of the structural components of EVs (phospholipid bilayers, membrane proteins, and receptors) and their application as drug delivery platforms. Depending on their cargo, engineered EVs can be designed to transport chemotherapeutics, nucleic acids, or proteins. Examples include EVs loaded with doxorubicin for glioblastoma (intravenous delivery), dinaciclib-loaded EVs for lung cancer (aerosol delivery), dendritic cell–derived EVs carrying the melanoma antigen gene (MAGE) for NSCLC (immunotherapy), macrophage-derived EVs encapsulating paclitaxel for multidrug-resistant tumors, and EVs engineered to deliver therapeutic genes to KRAS-mutant pancreatic cancer. These approaches highlight the versatility of EVs in oncology, with multiple delivery routes (intravenous, inhaled, oral) being explored to maximize their efficacy and minimize off-target toxicity. EV, extracellular vesicle; NSCLC, non–small cell lung cancer; MAGE, melanoma antigen gene; KRAS, Kirsten rat sarcoma viral oncogene homolog

Fig. 2. Exercise-derived extracellular vesicles (EVs) as mediators of antitumor effects. Schematic representation of systemic EVs released during physical activity from multiple tissues, including skeletal muscle, hepatocytes, endothelial cells, immune cells, and adipose tissue. These vesicles, enriched with myokines, microRNAs, metabolic enzymes, and heat shock proteins, enter the circulation and influence both tumor biology and cardiac function. (A) In vivo studies have shown that exercise-induced EVs reduce primary tumor growth, delay lung metastasis, modulate macrophage polarization (M1/M2 shift), and decrease the tumor burden in triple-negative breast cancer models. (B) In vitro experiments with human exercise-derived EVs demonstrated decreased viability of colon cancer cells (HT-29), inhibited migration and proliferation, and induced intrinsic apoptosis in an exercise-intensity–dependent manner. (C) Skeletal muscle–derived EVs deliver antitumor proteins and microRNAs (e.g., IGFBP6/7, PEDF, and myokines), suppress tumor proliferation, migration, and invasion, and exert broad-spectrum antimetastatic effects while increasing chemosensitivity

Fig. 3. Exercise-induced cardioprotection and potential contribution of ExEVs in oncology. Schematic representation of anthracycline-associated cardiotoxicity and the potential involvement of ExEVs in exercise-induced cardioprotective responses. Anthracycline-based chemotherapy may induce cardiac injury through cardiomyocyte apoptosis, oxidative stress, inflammation, and mitochondrial dysfunction. PA activates a coordinated multi-organ response involving exercise-responsive tissues, including endothelium, skeletal muscle, adipose tissue, liver, immune cells, and the nervous system, promoting the release of ExEVs with highly regulated, tissue-specific molecular cargo. These EVs have been reported to modulate key pathways in cardiomyocytes, including oxidative stress, inflammatory signaling, mitochondrial function, and cell survival. EVs, extracellular vesicles; ExEVs, exercise-derived extracellular vesicles; PA, physical exercise; miRNAs, microRNAs