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

ABSTRACT 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.