Self-assembled metal-coordinated nanoparticles for synergistic energy metabolism inhibition and low-temperature photothermal therapy.

Photothermal therapy has been observed to upregulate the heat shock protein 70 (HSP 70) expression in tumor cells, consequently diminishing the anti-tumor efficacy of the treatment. The expression of HSP 70 is intricately linked to the adenosine triphosphate (ATP) levels within tumors, suggesting that modulating energy metabolism could potentially enhance the effectiveness of photothermal therapy. To address these challenges, ATO-QUE-Fe²⁺-PVP K30 nanoparticles (AQFP NPs) were synthesized through the coordinated self-assembly of the oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO) and the glycolysis inhibitor quercetin (QUE) with ferrous ions (Fe²⁺) for synergetic energy depletion and low-temperature photothermal therapy (LTPTT). The synthesized AQFP NPs exhibited a small particle size and demonstrated high encapsulation efficiency of ATO and QUE. AQFP NPs could effectively downregulate the expression of HSP 70 by inhibiting the activity of mitochondrial complex Ⅲ and hexokinase Ⅱ (HK Ⅱ) to inhibiting suppress mitochondrial OXPHOS and glycolytic pathways in 4T1 cells, respectively. This inhibition resulted in a reduction of ATP levels within tumor cells, subsequently leading to decreased expression of HSP 70 and enhancing the therapeutic efficacy of LTPTT. Furthermore, AQFP NPs can remarkably inhibit the growth of tumors when subjected to laser irradiation. Furthermore, the analysis of blood biochemical indices and hematoxylin and eosin (H&E) staining of major organs suggested that AQFP NPs exhibit a preferable in vivo safety profile. In conclusion, the anti-tumor efficacy of LTPTT could be substantially enhanced by concurrently inhibiting OXPHOS and glycolysis, thereby offering an innovative therapeutic for the clinical treatment of tumors.