Manganese-based nanozymes as broad-spectrum antioxidants against cisplatin-induced skeletal muscle atrophy

Chemotherapeutic drugs used for patients with malignant diseases often lead to skeletal muscle atrophy, which is a devastating side effect and contributes to decreased quality of life and survival. Overproduction of reactive oxygen species (ROS) and chronic unresolved inflammation have been shown as major drivers of chemotherapeutic agents-induced skeletal muscle atrophy. Nanomedicine that can scavenge ROS and relieve inflammation have the potential to treat chemotherapy-associated muscle wasting. Here we prepared a simple and efficient one-step development of engineered manganese-based nanozymes (Mn-PDAs) and demonstrated their potential as therapeutic agents for chemotherapy-induced muscle atrophy. Mn-PDAs with multiple enzyme-mimicking activities could effectively scavenge abroad spectrum of ROS and repress pro­inflammatory cytokines production in vitro . Mn-PDAs could also efficiently suppress ROS-induced myotube apoptosis, promote mitochondrial biogenesis, ameliorate mitochondrial dysfunction and exert a robust anti-inflammatory effect by inhibiting the infiltration of pro-inflammatory M1 macrophages in the local muscle environment, therefore alleviating cisplatin-associated muscle atrophy in mice. Mechanistically, transcriptomic analysis revealed that PI3K/AKT/mTOR signal pathway activation involved in Mn-PDAs-prevented muscle atrophy. Our study presents a therapeutic strategy against chemotherapy-induced muscle atrophy, and also highlights the potential of Mn-PDAs­based therapeutics to treat other oxidative stress-associated diseases.