Abstract

Abstract Reactive oxygen species (ROS)-associated anticancer approaches usually suffer from two limitations, i.e., insufficient ROS level and short ROS half-life. Nevertheless, no report has synchronously addressed both concerns yet. Herein, a multichannel actions-enabled nanotherapeutic platform using hollow manganese dioxide (H-MnO 2 ) carriers to load chlorin e6 (Ce6) sonosensitizer and CO donor (e.g., Mn 2 (CO) 10 ) has been constructed to maximumly elevate ROS level and trigger cascade catalysis to produce CO. Therein, intratumoral H 2 O 2 and ultrasound as endogenous and exogeneous triggers stimulate H-MnO 2 and Ce6 to produce •OH and 1 O 2 , respectively. The further cascade reaction between ROS and Mn 2 (CO) 10 proceeds to release CO, converting short-lived ROS into long-lived CO. Contributed by them, such a maximumly-elevated ROS accumulation and long-lived CO release successfully suppresses the progression, recurrence and metastasis of lung cancer with a prolonged survival rate. More significantly, proteomic and genomic investigations uncover that the CO-induced activation of AKT signaling pathway, NRF-2 phosphorylation and HMOX-1 overexpression induce mitochondrial dysfunction to boost anti-tumor consequences. Thus, this cascade catalysis strategy can behave as a general means to enrich ROS and trigger CO release against refractory cancers. Graphic Abstract