Mitochondria-Homing Nanomedicine Triggers Metabolic Collapse for Synergistic Treatment of Metformin-Resistant Breast Cancer

Metformin (Met) is recognized as a star drug with multi-pathway anti-cancer potential, yet conventional Met-based therapies remain limited by insufficient targeting and failure to reverse adaptive metabolic reprogramming. Triple-negative breast cancer (TNBC) cells develop Met resistance via dysregulated mitochondrial oxidative phosphorylation (OXPHOS) and metabolic flexibility. Herein, we present a mitochondrial metabolic reprogramming strategy that fully exploits the dependence of TNBC cells on OXPHOS to induce selective biological energy collapse. A mitochondria-targeted multifunctional nanoplatform (M@AMT NPs) was constructed via integrating ammonia borane (AB), Met, and triphenylphosphine (TPP) onto molybdenum disulfide (MoS 2 ) nanoflowers. M@AMT NPs equipped with pH/NIR-responsive modules enables synchronized hydrogen-photothermal-chemodynamic therapy. TPP moiety enables precise mitochondrial localization, triggering a self-amplifying therapeutic cycle wherein local hydrogen/photothermal/chemodynamic perturbation-induced mitochondrial dysfunction abrogates OXPHOS and consequently exacerbates subsequent metabolic catastrophe. Mitochondria-localized H 2 synergizes with Met to disrupt ATP production, downregulate heat shock proteins, and restore Met sensitivity. In contrast to conventional resistance-reversing interventions, this approach exploits the intrinsic metabolic adaptability of resistant cancer cells to provoke self-driven collapse. This work establishes a new class of metabolically adaptive nanomaterials capable of reprogramming mitochondrial energy metabolism, offering a versatile platform for precision therapy against Met-resistant TNBC.