A Metal‐Phenolic Nanocluster Orchestrates Mito‐Ca 2+ Metabolic Autonomy for Tumor Ca 2+ Interference Therapy
Ronglong Chen, Jia Huang, Yuepeng Wang, Shucong Yao, Fei Wu, Juan Liu, Chunxue Song, Li Lin, Xijun Lin, Yingjie Deng, Chao Zhang, Zhiquan Huang, Zixian Huang, Lisi XieABSTRACT
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.