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

Abstract Activation of ubiquitously expressed inositol trisphosphate receptors (IP ₃ Rs) represents a compelling Ca ²⁺ overload strategy for cancer treatment, featuring intrinsic biosafety, a steep 15 000‐fold Ca ²⁺ 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 H ₂ O ₂ generation via a direct one‐step 2e ⁻ oxygen reduction reaction and ZIF‐67 protrusions for ^• OH production. H ₂ O ₂ oxidizes IP ₃ R cysteine residue to release endoplasmic reticulum (ER) Ca ²⁺ , which rapidly accumulates in mitochondria to cause mitochondrial Ca ²⁺ overload. Simultaneously, Ca ²⁺ 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 Ca ²⁺ overload‐mediated therapy via photocatalytic activation of tumor‐inherent Ca ²⁺ channels.