Nitric Oxide Modulating Calcium Store for Ca2+‐Initiated Cancer Therapy

Abstract Ions are essential to body, but sometimes can evolve into weapons to attack and destroy cells without systematic toxicity and drug resistance. Inspired by nitric oxygen as neurotransmitter in mediating Ca 2+ release, NO nanodonors with high photoreactivity and stability are constructed with upconversion nanoparticles (UCNPs) coated by zeolitic nitro‐/nitrile‐imidazole framework‐82 (ZIF‐82), capable of near‐infrared light (NIR) triggered NO generation and berbamine (BER) release, to achieve cancer therapy with the stored Ca 2+ in cells. The spatial confinement effect of 2‐nitroimidazole in ZIF‐82 enables NO‐releasing with tunable release kinetics. NO turns on the ryanodine receptors overexpressed in cancer cells for abrupt Ca 2+ elevation; meanwhile, berbamine (BER) turns Ca 2+ ‐excretion pumps off to inhibit calcium efflux, resulting in intracellular Ca 2+ overload induced apoptosis. This work provides the first example of regulating endogenous ions for cell killing, which holds promise as an effective cancer therapeutics that is complementary to traditional chemotherapeutics.