Excipient-free self-assembled nanotheranostics enable synchronous sensitization of tumoricidal photothermal and photodynamic therapies through mitochondrial metabolic intervention.

Aberrant tumor metabolism involves massive oxygen consumption to satisfy the increasing bioenergetic and biosynthetic requirements of malignant cells, severely compromising the efficacy of photothermal therapy (PTT) and photodynamic therapy (PDT). In this work, lonidamine (LND) and berberine (BBR) were chemically coupled via an alkyl chain to synthesize a novel antimetabolic anticarcinoma agent (BBR-LND), which was subsequently co-assembled with the photosensitizer indocyanine green (ICG) to form excipient-free nanotheranostics (BLI NPs) for sensitization to dual PTT/PDT treatment. The favorable stability of BLI NPs enabled efficient tumor accumulation through passive targeting, while specific drug release was triggered upon endocytosis into the acidic endo/lysosomes of cancer cells. Upon liberation, BBR-LND selectively accumulated in mitochondria and effectively inhibited electron transport chain complexes I and II, thereby suppressing mitochondrial respiration and adenosine triphosphate production, ultimately reversing tumor hypoxia and silencing intratumoral heat shock protein 70. Consequently, the susceptibility of tumor cells to ICG-mediated PTT and PDT was significantly enhanced. Additionally, BBR-LND potently induced multilevel mitochondrial destruction, further counteracting tumor growth. Abundant studies demonstrated that BLI NPs robustly ablated tumor tissues under fluorescence/photoacoustic imaging-guided laser irradiation with excellent biosafety. This multifunctional nanotheranostic platform provides a simple yet versatile strategy to sensitize tumoricidal PTT/PDT combinations through mitochondrial metabolic intervention, with potential applications in other cancer therapies reliant on thermal effects or oxygen availability.