Gut-confined fullerene reprograms lactate metabolism to Rescue hypoxia-induced exercise intolerance.

Chronic hypoxia-induced exercise intolerance, a hallmark of high-altitude deterioration (HADT), lacks safe long-term therapies. Here, we develop an orally administered fullerene (C60) suspension that acts exclusively within the gastrointestinal tract due to negligible systemic absorption. Under chronic hypoxia, fullerene significantly reduced systemic lactate and enhanced exercise endurance without affecting muscle, hepatic, or renal lactate metabolism. Mechanistically, fullerene locally quenched reactive oxygen species (ROS) in intestinal epithelial cells, destabilizing hypoxia-inducible factor-1α (HIF-1α) and suppressing glycolysis. This reduced endogenous gut lactate production, alleviating lactate-mediated inhibition of muscle function. Crucially, fullerene concurrently preserved intestinal barrier integrity and mitigated hypoxia-induced damage. By confining therapeutic action to the gut-minimizing systemic exposure-this "local-to-systemic" strategy offers a fundamentally new solution for HADT with superior safety for chronic use, demonstrating broader potential for hypoxia-associated diseases.