Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents for treating a broad range of cancers. However, its dose-dependent cardiotoxicity remains a major clinical challenge, often limiting treatment and compromising patients' long-term cardiovascular health. Existing cardioprotective strategies are frequently constrained by limited efficacy or concerns that they may interfere with anticancer treatment.
Researchers from the Second Affiliated Hospital of Guangxi Medical University, the Nanozyme Engineering Laboratory at the Institute of Biophysics, Chinese Academy of Sciences, the Huazhong Branch of the National Center for Cardiovascular Diseases, and collaborating institutions have developed a chirality-engineered ruthenium nanozyme that protects against chemotherapy-induced cardiotoxicity by modulating the gut-heart axis.
Rather than directly targeting the heart, the researchers focused on the intestinal microenvironment, which has recently emerged as a critical regulator of cardiovascular health. Increasing evidence suggests that chemotherapy disrupts gut microbiota and host metabolism, leading to systemic oxidative stress, inflammation, and ultimately cardiac injury.
To identify the optimal nanozyme, the team systematically screened ruthenium nanozymes engineered with 20 natural amino acids. Among them, the L-methionine-engineered nanozyme (L-AEN) exhibited the strongest superoxide dismutase (SOD)- and catalase (CAT)-like cascade catalytic activities, efficiently scavenging reactive oxygen and nitrogen species. Further stereochemical engineering demonstrated that the L-enantiomer significantly outperformed its D- and DL-counterparts while maintaining excellent biocompatibility.
To enable oral administration, the nanozyme was encapsulated in an enteric formulation to generate L-AENC, allowing intestinal-targeted release and improved bioavailability. In a chronic mouse model of doxorubicin-induced cardiotoxicity, orally administered L-AENC markedly improved cardiac function, reduced myocardial injury, and alleviated systemic oxidative stress. Importantly, these cardioprotective effects were achieved without compromising the antitumor efficacy of doxorubicin.
Mechanistic studies revealed that L-AENC restored gut microbial homeostasis by enriching beneficial bacteria, particularly members of the Muribaculaceae family. Multi-omics analyses further showed that the treatment remodeled host metabolic pathways associated with tryptophan, glutathione, and butyrate metabolism while strengthening interactions between gut microbes and host metabolites. Together, these coordinated changes restored intestinal homeostasis and ultimately protected the heart through the gut-heart axis.
The findings demonstrate that stereochemical engineering is an effective strategy for enhancing nanozyme bioactivity. More importantly, the study establishes an orally administered nanozyme platform capable of simultaneously regulating gut microbiota, host metabolism, and systemic redox homeostasis. This work provides a new therapeutic strategy for preventing chemotherapy-associated cardiotoxicity and expands the potential of nanozyme-based therapeutics for diseases involving gut-organ axis dysfunction.
Science Bulletin
Experimental study