A systemic immunogenic reactor leveraging modified γ-cyclodextrins for photo-controlled cancer Ca2+ interference via modulating MICU1

Interference with calcium homeostasis provokes tumor cell death and immune response, providing a novel direction for tumor immunotherapy as a promising cancer treatment strategy. Nevertheless, most reported Ca²⁺-overloaded nanoinducers encounter challenges such as intricate preparation procedures, safety concerns arising from inorganic material input, and limited anti-tumor efficiency. Herein, we synthesized a biocompatible and pH-sensitive Ca-doped cyclodextrin metal-organic framework (Ca/K-MOF) as a carrier, which was then loaded with photosensitizer hypericin (HY) <i>via</i> a simple one-pot synthesis to form HY@Ca/K-MOF. To enhance the stability both <i>in vitro</i> and <i>in vivo</i>, we coated HY@Ca/K-MOF with a hydrophilic layer of PEG (^PEGHY@Ca/K-MOF). When exposed to 590 nm photoirradiation, ^PEGHY@Ca/K-MOF, with its pH-responsive dissociation, the Ca²⁺ and HY mediators released at the tumor site share the responsibility of triggering intracellular Ca²⁺ disturbances, which amplified the production of reactive oxygen species (ROS) and led to mitochondrial calcium overload through modulating mitochondrial MICU1 function. Under photocontrol, this interplay between ROS generation and mitochondrial calcium overload created a bidirectional amplification effect, where each process reinforced the other, subsequently eliciting a pyroptosis-evoked immune response. Significantly, this newly constructed delivery platform effectively suppressed both primary and distant tumors without the need for additional immunological interventions. In summary, this Ca²⁺-doped MOF-based nanomaterial provides a promising approach for efficient tumor photo-controlled mitochondrial Ca²⁺ overload-pyroptosis immunotherapy.