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

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 Ca2+ 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 Ca2+ 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 Ca2+ elevation; meanwhile, berbamine (BER) turns Ca2+‐excretion pumps off to inhibit calcium efflux, resulting in intracellular Ca2+ 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. An in situ Ca2+ regulation nanosystem is constructed with upconversion nanoparticles (UCNP) coated by ZIF‐82 with berbamine (BER). UCNP up‐converts NIR to UV light for activation of NO generation and BER release. NO turns on ryanodine receptors for Ca2+ elevation; BER turns off calcium pumps to inhibit the Ca2+ efflux. NO and BER synergistically lead to calcium‐apoptosis for cancer therapy.