Mitochondria‐Targeted Nanomotor: H 2 S‐Driven Cascade Therapy for Hepatocellular Carcinoma

作者：Chengcheng Li, Xiaodong Ma, Shiji Fang, Biao Chen, Xinru Wang, Ling‐Yun He, Xin Yang, Yuanqiang Li, Jessica M. Rosenholm, Zhongwei Zhao, Jiansong Ji, Hongbo Zhang · 发表于：Advanced Materials · 年份：2025 · DOI：10.1002/adma.202513757 · 被引用次数：3 · 研究领域：Nanoplatforms for cancer theranostics、Micro and Nano Robotics、Cancer Research and Treatments

Abstract Despite advances in combination therapies for cancer treatment, most strategies rely on modular‐additive designs that lack dynamic molecular cues to achieve intrinsic synergy. Herein, a mitochondrial‐targeted nanoplatform is introduced that orchestrates photodynamic therapy (PDT), mild photothermal therapy (mPTT), and enzyme dynamic therapy (EDT) into a self‐amplifying cascade network through gasotransmitter (H 2 S)‐driven metabolic reprogramming. It is constructed from an Au 2 Pt core with a surface functionalized mesoporous silica shell loaded with photosensitizers, encapsulated within a tumor cell membrane (Au 2 Pt@4sMSN/PS‐TPP@CM). Upon GSH exposure, nanomotors produce H 2 S to boost diffusive motion, while TPP targeting directs this motility toward mitochondria, enabling efficient mitochondrial accumulation (internalization of >100 nm nanoparticles). Subsequently, mitochondrial targeted H 2 S releasing‐mediated suppression of oxidative phosphorylation amplifies PDT efficacy; HSP70 downregulation enables mPTT; and hyperactive glycolytic metabolism fuels EDT. Furthermore, these enhanced modalities also interconnect in a positive feedback loop: mPTT‐derived hyperthermia accelerates EDT‐catalyzed oxygen generation for PDT, while mitochondria‐localized PDT further inhibits HSP70 to boost mPTT. Ultimately, these interconnected molecular cues establish an H 2 S‐driven, self‐reinforcing therapeutic loop that enables effective eradication of hepatocellular carcinoma. ...