A Snakeberry‐Inspired Photocatalytic Nanoreactor Activates Endogenous Ca ²⁺ Store for Ca ²⁺ Overload‐Mediated Cancer Therapy

Activation of ubiquitously expressed inositol trisphosphate receptors (IP₃Rs) represents a compelling Ca²⁺ overload strategy for cancer treatment, featuring intrinsic biosafety, a steep 15 000-fold Ca²⁺ flux gradient, and pan-cancer applicability. However, it remains underexplored due to challenges in developing on-demand and sustainable activation modalities that ensure treatment reproducibility while preventing off-target toxicity. This study presents a novel snakeberry-like nanoreactor (APF@ZIF-67) with a porous photocatalytic core for H₂O₂ generation via a direct one-step 2e^- oxygen reduction reaction and ZIF-67 protrusions for ^•OH production. H₂O₂ oxidizes IP₃R cysteine residue to release endoplasmic reticulum (ER) Ca²⁺, which rapidly accumulates in mitochondria to cause mitochondrial Ca²⁺ overload. Simultaneously, Ca²⁺ dyshomeostasis and oxidative stress co-activate ER stress and subsequent pro-apoptotic unfolded protein response pathway. ER stress and mitochondrial damage activate inflammatory response and inflammation-driven senescence, eventually leading to cell apoptosis. Importantly, damaged mitochondrial transfer between tumor cells induces bystander effects and amplifies therapeutic effects. Moreover, dark brown APF@ZIF-67 enables mild photothermal therapy, synergistically enhancing tumor ablation. In vivo, APF@ZIF-67 efficiently accumulates in tumors and achieves near-complete eradication without systemic toxicity. Collectively, this study proposes a novel pan-cancer endogenous Ca²⁺ overload-mediated therapy via photocatalytic activation of tumor-inherent Ca²⁺ channels.