Leveraging Tissue‐Derived Extracellular Vesicles for Regenerative Medicine

Tissue-derived extracellular vesicles (Ti-EVs) encapsulate the complex molecular signature of their native microenvironment, serving as critical mediators for tissue homeostasis and regeneration. This review provides a state-of-the-art overview of Ti-EV biology, critically evaluating current evidence from the liver, heart, adipose tissue, and skeletal muscle while identifying key challenges and future perspectives for clinical translation. We first categorize current isolation technologies by their validation status in the Ti-EV context, and then survey organ-specific functional profiles with emphasis on the functional shifts that accompany transitions between physiological and pathological states, as well as inter-organ communication. Cross-tissue comparison reveals conserved cargo classes, shared signaling pathways, and five recurrent regenerative mechanisms, including cell cycle regulation, metabolic reprogramming, microenvironment remodeling, angiogenesis, and programmed cell death control. These patterns point to three overarching principles: cargo composition encodes tissue identity, effector mechanisms are drawn from a constrained functional repertoire, and functional output is calibrated by tissue states. Engineering strategies for cargo reprogramming, controlled delivery, and targeted modification are discussed alongside bottlenecks in scalable production and regulatory compliance. This integrated framework positions Ti-EVs as context-dependent signaling systems and highlights single-vesicle analysis, smart cargo editing, and personalized precision approaches as key directions for clinical translation.