Chemodynamic
therapy represents a distinct anti-
tumor strategy by activating intratumoral chemical catalytic reactions to produce highly toxic
reactive oxygen species (ROS) from non-/limited-toxic nanocatalysts. However, the low efficacy of ROS generation still remains a major challenge for further clinical translation. Herein, a liposomal nanosystem which simultaneously encapsulated
copper peroxide nanodots (CPNs) and
artemisinin (ART) was constructed for autophagy-enhanced and ferroptosis-involved
cancer cell death owing to Cu-based dual catalytic strategy. To be specific, the CPN components, served as a H2O2 self-supplying platform, release H2O2 and Cu2+ under acidic
tumor environment and endogenously generate .
OH via Fenton-like reaction (catalytic reaction I). In addition, Cu2+ species catalyze ART components to produce ROS radicals (catalytic reaction II), further augmenting the intracellular oxidative damage and
lipid peroxide accumulation, leading to
cancer cell death. Specifically, ART also acted as a potent autophagy inducer increasing the level of intracellular
iron pool through degradation of
ferritin, which could promote
cancer cell ferroptosis, producing the best
antineoplastic effect. After accumulation into the
tumor sites, ultrasound irradiation was applied to trigger the release of CPNs and ART from liposomal nanosystems, and amplify the efficacy of catalytic reaction for maximum
therapeutic effect. Both in vitro and in vivo therapeutic outcomes suggest the outstanding autophagy-augmented ferroptosis-involved
cancer-therapeutic efficacy, which was further corroborated by transcriptome sequencing. In this work, Cu was firstly proven to trigger ART to produce ROS species, but also provide a TME-responsive nanoplatform for potentially suppressing
tumor growth by autophagy-augmented ferroptosis-involved
cancer nanotherapy.