Step-by-step Guided Nanoplatforms for Efficiently Sensitizing Phototherapy via Mitochondrial Metabolic Reprogramming

Abstract Background Phototherapy, a promising chemotherapy alternative, has been widely utilized for cancer treatment. However, heat shock protein (HSP70) mediated-heat tolerance in photothermal therapy (PTT), and the attenuated therapeutic effect of photodynamic therapy (PDT) in the hypoxic tumor microenvironment still limit its clinical applications, where both processes are intimately linked to energy metabolism. Results We designed a site-specific nanoplatform (CS@ATO/CHC/T780 NPs) modulating energy metabolism to down-regulate the expression of HSP70 and alleviate hypoxia for enhanced phototherapy by integrating a mitochondria-targeted triphenylphosphine (TPP) derivative (T780), mitochondrial electron transport chain inhibitor atovaquone (ATO) and monocarboxylic acid transporter 1 (MCT1) inhibitor α-cyano-4-hydroxycinnamate (CHC), and modified with chondroitin sulfate (CS). Mechanistically, CS and TPP-tailored IR780 were used to achieve site-specific delivery to tumor tissues and mitochondria in tumor cells, respectively. After efficient cellular internalization, the nanoplatform could effectively disassemble to release cargoes in the acid tumor microenvironment. ATO, a mitochondrial electron transport chain complex III inhibitor, could reduce the production of intracellular adenosine triphosphate (ATP) and further downregulate the expression of HSP70 to overcome the thermo-resistance of PTT. Meanwhile, CHC could reduce the uptake rate of lactic acid (LA) to save oxygen consumption for improving the effectiveness of PDT. Conclusion The CS@ATO/CHC/T780 NPs exhibits excellent anticancer activity and good biosafety in vitro and in vivo , providing a prospective strategy for efficient phototherapy by manipulating energy metabolism.