A Metal‐Phenolic Nanocluster Orchestrates Mito‐Ca ²⁺ Metabolic Autonomy for Tumor Ca ²⁺ Interference Therapy

ABSTRACT Mitochondrial Ca ²⁺ (mito‐Ca ²⁺ ) interference, an effective mitochondria destruction strategy in cancer treatment, suffers from precise self‐protective Ca ²⁺ metabolic autoregulation by Ca ²⁺ channels. Direct regulation of Ca ²⁺ channels‐mediated mito‐Ca ^{2 +} metabolic autonomy will overcome this obstacle for advanced Ca ²⁺ interference therapy. Here, we engineer a novel meta‐phenolic nanocluster (TCMH) by self‐assembly of polyphenols encapsulating mitochondrial calcium uniporter (MCU) modulators (mitofusin 1 siRNA (siMFN1), H ₂ S donor) and Ca ²⁺ via metal‐phenolic coordination. After cellular internalization, the acid‐responsive disassembly of TCMH triggers the release of its’ payloads. TCMH promotes a rapid surge in mito‐Ca ²⁺ via synergistic MCU activation by siMFN1‐mediated mitochondrial fusion suppression and released H ₂ S. Furthermore, integrating with H ₂ S‐mediated reactive oxygen species (ROS) enrichment, this Ca ²⁺ ‐based TCMH forms a self‐amplifying ROS‐Ca ^{2 +} positive feedback loop to sensitize mitochondrial apoptosis. TCMH potently benefits robust antitumor therapeutics in both oral squamous cell carcinoma orthotopic and patient‐derived xenograft models. Together, a powerful MCU‐mediated mito‐Ca ²⁺ metabolic autonomy modulation tactic is highlighted here to optimize precise tumor Ca ²⁺ interference therapy.