Precision mitochondrial reprogramming a ROS-amplifying Pt(IV) nanoplatform potentiates tri-modal therapy to overcome Pt resistance in HCC.

Mitochondrial dysfunction plays a critical role in hepatocellular carcinoma (HCC) progression. This study develops a glutathione-responsive Pt(IV)-artesunate (ART) prodrug (Pt-ART) that co-releases cisplatin and ART in the tumor microenvironment, synergizing DNA damage and iron-dependent ROS generation for combined chemotherapy and chemodynamic therapy. The prodrug is encapsulated into a ROS-responsive, fluorinated polyethyleneimine-chlorin e6-based polycationic nanoparticle, coated with polyethylene glycol-chondroitin sulfate for enhanced tumor targeting the EPR effect, CD44 receptor-mediated uptake, and mitochondrial accumulation. This nanoplatform effectively inhibits Drp1 expression, induces mitochondrial membrane depolarization, and demonstrates potent triple-modality therapy combining chemotherapy, chemodynamic therapy, and photodynamic therapy. Our work provides an innovative strategy integrating herbal medicine with nanotechnology to overcome limitations of conventional Pt-based therapies.