Biomimetic nanoparticle synchronizing pyroptosis induction and mitophagy inhibition for anti-tumor therapy

Inducing pyroptosis in cancer cells can result in a strong anti-tumor immune response. Our preliminary study indicates that pyroptosis can be temporarily strengthened by disrupting mitochondria, but ultimately diminished by defensive mitophagy. Here, this study reports a nano-system camouflaged with hybrid membranes consisting of homologous cell membrane and corresponding mitochondrial membrane, which is used to deliver a drug complex Ca@GOx consisting of calcium phosphate and glucose oxidase. By taking advantage of the homing effects of cell membrane and the orientated fusion mechanism of subcellular membrane, the nano-system is able to deliver Ca@GOx to mitochondria, induce mitochondrial Ca²⁺ overload and generate significant levels of ROS, thus leading to pyroptosis. However, it's found that this system exhibits limited anti-tumor effects in vivo due to the compensatory activation of mitophagy serving as negative feedback to pyroptosis. To address this issue, mitophagy-inhibiting chloroquine is loaded into nanoparticles to intensify pyroptosis. As a result, the combination significantly promotes tumor infiltration of CD8⁺T cells and improves anti-tumor effects. Together, this study establishes a rational combination of targeted mitochondria disruption and mitophagy blockage for effective pyroptosis-based therapy.