Mitochondria-Targeted Nanomotor: HS-Driven Cascade Therapy for Hepatocellular Carcinoma.

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 (HS)-driven metabolic reprogramming. It is constructed from an AuPt core with a surface functionalized mesoporous silica shell loaded with photosensitizers, encapsulated within a tumor cell membrane (AuPt@4sMSN/PS-TPP@CM). Upon GSH exposure, nanomotors produce HS to boost diffusive motion, while TPP targeting directs this motility toward mitochondria, enabling efficient mitochondrial accumulation (internalization of >100 nm nanoparticles). Subsequently, mitochondrial targeted HS 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 HS-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.