Chirality-engineered nanozymes orchestrate gut microbiota-host metabolism to shield against cardiotoxicity during cancer chemotherapy via the gut-heart axis.

Doxorubicin-induced cardiotoxicity remains a critical challenge in cancer chemotherapy, as current strategies rarely balance antitumor efficacy with prevention of systemic side effects. Herein, we develop a chiral amino acid-engineered ruthenium-based nanozyme platform for gut-heart axis-mediated cardioprotection. Systematic screening of 20 amino acids identifies L-Met as the optimal ligand, yielding L-AEN with superior superoxide dismutase- and catalase-like cascade activities and efficient scavenging of ROS and RNS. Chirality engineering further endows L-AEN with markedly enhanced antioxidant performance compared with its D- and DL-counterparts, while maintaining excellent biocompatibility. After enteric encapsulation to form L-AENC, oral administration enables intestinal-targeted release and improves in vivo bioavailability. In a doxorubicin-induced chronic cardiac injury model, L-AENC significantly improves cardiac function, reduces myocardial damage, and suppresses systemic oxidative stress without affecting the antitumor efficacy of doxorubicin. Mechanistically, L-AENC restores gut microbiota homeostasis by enriching beneficial taxa, particularly Muribaculaceae, and reshapes host metabolic profiles, notably involving tryptophan, glutathione, and butyrate metabolism, thereby strengthening gut microbiota-metabolite interactions. Collectively, this work demonstrates that a chirality-engineered nanozyme platform coordinates gut microbiota and host metabolism to protect against chemotherapy-induced cardiotoxicity via the gut-heart axis, highlighting stereochemical engineering as an effective strategy for nanozyme-based therapeutic design.