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

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. Collectively, this study identifies mitochondria as the biological initiator and signal integrator for multimodal therapy, delivering a distinctive paradigm to overcome the limitations of conventional combination therapies.