Engineering mitochondrial uncoupler synergistic photodynamic nanoplatform to harness immunostimulatory pro-death autophagy/mitophagy

Generally, autophagy/mitophagy, as a highly conserved lysosomal-based catabolic pathway, compromises the photodynamic therapy (PDT) efficiency by increasing the adaptation of tumor cells toward reactive oxygen species (ROS)-triggered protein damages and mitochondrial destruction. On the other hand, excessively activated autophagy/mitophagy cascades can provoke autophagic cell death and promote the endogenous antigens release of dying cells, thus playing a vital role in initiating the antitumor immune responses. To harness the exquisite immunomodulating effect of pro-death autophagy/mitophagy, we rationally constructed a MnO2 shell-coated multifunctional porphyrinic metal-organic framework (MOF) to load carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The wrapped MnO2 shell could not only prevent premature release of CCCP during blood circulation but also conquer tumor hypoxia by catalyzing the decomposition of intratumoral H2O2. After entering tumor cells, the MnO2 shell could scavenge over-expressed glutathione (GSH), resulting in burst CCCP release and GSH-depletion/O2-generation enhanced PDT. More importantly, the released CCCP acts as a mitochondrial uncoupler can elicit mitochondrial depolarization and mitophagy, which could significantly boost the autophagy/mitophagy levels generated during PDT and consequently convert the pro-survival autophagy/mitophagy to pro-death, leading tumor cells to autophagic and immunogenic cell death. In vivo results reveal that the CCCP synergistic PDT could induce excessive immunostimulatory autophagy/mitophagy associated with T-cell responses and immunological memory, leading to complete ablation of primary tumors and prevention of tumor recurrence and lung metastasis. The effectiveness of this strategy may highlight the pro-death role and immunomodulating effect of autophagy/mitophagy in cancer therapy, providing a novel yet versatile avenue to enhance the efficacy of cancer treatments.