A Metal-Phenolic Nanocluster Orchestrates Mito-Ca²⁺ Metabolic Autonomy for Tumor Ca²⁺ Interference Therapy

Mitochondrial Ca²⁺(mito-Ca²⁺) interference, an effective mitochondria destruction strategy in cancer treatment, suffers from precise self-protective Ca²⁺ metabolic autoregulation by Ca²⁺ channels. Direct regulation of Ca²⁺ channels-mediated mito-Ca^{2 +} metabolic autonomy will overcome this obstacle for advanced Ca²⁺ 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), H₂S donor) and Ca²⁺ 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-Ca²⁺ via synergistic MCU activation by siMFN1-mediated mitochondrial fusion suppression and released H₂S. Furthermore, integrating with H₂S-mediated reactive oxygen species (ROS) enrichment, this Ca²⁺-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-Ca²⁺ metabolic autonomy modulation tactic is highlighted here to optimize precise tumor Ca²⁺ interference therapy.