Tumor Microenvironment Responsive Hollow Nanoplatform for Triple Amplification of Oxidative Stress to Enhance Cuproptosis‐Based Synergistic Cancer Therapy

Abstract Cuproptosis is a recently discovered form of programmed cell death and shows great potential in cancer treatment. Herein, a copper‐dithiocarbamate chelate‐doped and artemisinin‐loaded hollow nanoplatform (HNP) is developed via a chelation competition‐induced hollowing strategy for cuproptosis‐based combination therapy. The HNP exhibits tumor microenvironment‐triggered catalytic activity, wherein liberated Cu2+ catalyzes artemisinin and endogenous H2O2 to produce C‐centered radicals and hydroxyl radicals, respectively. Meanwhile, the disulfide bonds‐rich HNP can deplete intracellular glutathione, thus triply amplifying tumor oxidative stress. The augmented oxidative stress sensitizes cancer cells to the cuproptosis, causing prominent dihydrolipoamide S‐acetyltransferase oligomerization and mitochondrial dysfunction. Moreover, the HNP can activate ferroptosis via inhibiting GPX4 activity and trigger apoptosis via dithiocarbamate‐copper chelate‐mediated ubiquitinated proteins accumulation, resulting in potent antitumor efficacy. Such a cuproptosis/ferroptosis/apoptosis synergetic strategy opens a new avenue for cancer therapy.