Remote mobilization of gut Tregs exosomes serves as nanoshuttles for targeted cardioprotection against ischemia/reperfusion injury by ginseng polysaccharides.

Myocardial ischemia-reperfusion injury (MIRI) remains a critical clinical condition with limited preventive and therapeutic strategies, underscoring the need for novel interventions. The gut-heart axis and exosomal crosstalk hold therapeutic promise for cardioprotection, yet the fundamental question of which specific gut cells release the beneficial exosomes is unanswered. This study aimed to elucidate whether ginseng polysaccharides WGPA exert remote cardiac protection by regulating intestinal immune homeostasis, specifically through promoting the release of exosomes from regulatory T cells (Tregs). Using integrated in vivo and in vitro models, we evaluated the protective effects of WGPA against MIRI. The results demonstrated that WGPA pretreatment significantly attenuated myocardial injury and improved cardiac function. Mechanistically, WGPA selectively activated intestinal Tregs and enhanced the release of HSP70-enriched exosomes. These exosomes entered systemic circulation and were delivered to the heart, where surface HSP70 interacted with TLR4 on cardiomyocytes, activating downstream protective signaling pathways and ultimately suppressing cardiomyocyte death and inflammatory responses. Our study reveals for the first time a complete mechanism by which medicinal plant polysaccharides confer cross-organ cardioprotection via the "intestinal Tregs-exosome-heart" axis, providing a novel theoretical basis and a potential intervention strategy for the prevention and treatment of MIRI.