Abstract: Objective To investigate the mechanisms of extracellular vesicles (EVs) in Traditional Chinese Medicine (TCM) against “thromboinflammation” in ischemic cardio-cerebrovascular diseases, analyze the way TCM reshapes EV communication networks, and challenges to clinical translation. Methods Literature regarding TCM regulation of EVs was reviewed to summarize strategies for “addressing the root cause of problems” and “precision loading” that affected the biogenesis and delivery of EVs. Constraints imposed by in vivo metabolic complexity and EV heterogeneity on evaluation of clinical efficacy were analyzed. Results TCM remodeled the thromboinflammatory microenvironment primarily through two strategies: ① “addressing the root cause of problems”, which could help improve mitochondrial metabolism in parent cells to enhance protective EVs and curb pro-thrombotic EV generation while interpreting the biological basis of “Qi-boosting” (Yiqi), and ② “precision loading”, which meant physically blocking pathogenic miRNAs from loading into EVs, severing the inflammation-coagulation cascade and embodying “blood-activating” (Huoxue) signal decoupling. However, the “black box” of in vivo metabolism and high background noise of blood EVs remained technical barriers to translation. Conclusion EVs are crucial mediators for TCM interventions in thromboinflammation. TCM can not only optimize endogenous EV activity, but also use engineered EVs for precise delivery. It is recommended that evaluation standards be established for specific EVs based on single-particle analysis so as to promote the transition of TCM research toward precise “cell communication remodeling”.

Key words: Traditional Chinese Medicine, Extracellular Vesicles, Ischemic Cardio-Cerebrovascular Diseases, Thromboinflammation, Mechanism, Clinical Translation