Rare-earth upconversion luminescence mediate mitochondrial endogenous calcium overload-induced pyroptosis for tumor immunotherapy

Mitochondrial Ca 2+ overload is a promising strategy to induce pyroptosis. However, exogenous introduction of Ca 2+ -regulation is often inefficient due to the body’s homeostatic regulatory properties and the acidic microenvironment of tumor. Here, we achieve efficient mitochondrial endogenous Ca 2+ overload for inducing pyroptosis by controlling the extracellular Ca 2+ influx and endoplasmic reticulum (ER) Ca 2+ leakage. Specifically, on the one hand, the singlet oxygen produced by near-infrared irradiation of upconversion nanoparticles stimulate the opening of TRPV1 channel on the cell membrane surface to influx Ca 2+ ; on the other hand, the opening of Ryanodine Receptor channel on the ER by tunicamycin leads to Ca 2+ leakage. Under the dual action of extracellular Ca 2+ influx and ER Ca 2+ leakage, the surge of Ca 2+ concentration in the cytoplasm further induces Ca 2+ overload in mitochondria, which triggers pyroptosis through the caspase 1/gasdermin D-dependent channel. Importantly, the onset of pyroptosis induces a strong immune response, ultimately enabling not only efficient tumor therapy, but also inhibition of lung metastasis.