Harnessing Natural Extracellular Vesicles to Combat Age-Related Diseases: From Aging Drivers to Therapeutic Opportunities.

Aging is a complex biological process that leads to a growing burden of age-related diseases (ARD). Cellular senescence, which involves irreversible cell cycle arrest and the release of senescence-associated secretory phenotype (SASP), plays a central role in aging and the development of ARD. Natural extracellular vesicles (NEVs) refer to vesicles that derived from cells, organs and body fluids without artificial interventions. In recent years, NEVs have gained attention as mediators of intercellular communication, and showed multifunctional potential in regulating cellular senescence and ARD. On the one hand, these vesicles are capable of spreading senescence signals by transferring molecules such as miRNAs, proteins, and DNA fragments. On the other hand, NEVs derived from animal cells, body fluids, plant cells, and bacteria have demonstrated potential anti‑aging effects. This review synthesizes research findings from the past two decades, with a particular focus on studies published in the last five years that elucidate the molecular mechanisms by which NEVs regulate cellular senescence. This review aims to summarize various applications (biomarkers, drug delivery vehicles, direct therapeutic agents) of NEVs in major ARD, including neoplasms, cardiovascular diseases, neurodegenerative disorders, bone diseases, and diabetes. Several challenges including standardizing production, targeted delivery, mechanism exploration, and clinical translation are also discussed. Combining bioengineering, multi-omics technologies, and improved model systems could be important to fully utilize the potential of NEVs, and offer precise, safe, and effective strategies for ARD therapy.