Oral Bioinspired Peroxisome‐Engineered Probiotics for Modulating Gut Microbiota Homeostasis and Alleviating Cardiac Chemotherapy Toxicity

ABSTRACT Anthracyclines such as doxorubicin (DOX) are widely used in cancer chemotherapy but their clinical utility is severely limited by cumulative, dose‐dependent, and largely irreversible cardiotoxicity. Mounting evidence suggests that DOX disrupts intestinal barrier integrity and microbial homeostasis, aggravating systemic oxidative stress and accelerating myocardial injury through the gut–heart axis. Probiotics offer a potential strategy to stabilize the intestinal microenvironment, yet their fragile nature and poor survival in the gastrointestinal tract hinder clinical translation. Here, we present an orally administrable bioinspired peroxisome engineered probiotic (BPEP) as a safe and effective therapeutic platform. Ruthenium‐based nanozymes with superoxide dismutase‐like and catalase‐like activities were encapsulated in a lipid shell to form bioinspired peroxisomes (BP) and covalently anchored onto Escherichia coli Nissle 1917 . The lipid shell enhances probiotic resistance to gastric acid, bile salts, and reactive oxygen species, improving gastrointestinal survival and colonization. Acting as a living carrier, probiotics deliver BPs to the intestinal barrier, where they synergistically scavenge reactive oxygen and nitrogen species, restore tight junction integrity, and remodel microbial communities. In a chronic DOX‐induced cardiotoxicity mouse model, oral administration of BPEP effectively alleviated oxidative stress, preserved intestinal barrier function, stabilized microbial homeostasis, and ultimately improved cardiac function. This work establishes a bioinspired probiotic‐nanozyme hybrid strategy that overcomes the intrinsic limitations of natural probiotics and provides a promising approach for mitigating chemotherapy‐related cardiotoxicity via the gut‐heart axis.