Adenosine triphosphate-triggered aggregable DNA micelles for triple enhanced photothermal therapy in the second near-infrared window.

Despite significant advancements in photothermal therapy (PTT), its clinical treatment efficacy for cancer remains constrained because of the limited tissue penetration of light as well as the thermal resistance of tumor cells. To achieve efficient PTT activated under near-infrared II (NIR-II) light irradiation, here we developed a triple-enhanced NIR-II PTT system through the design of ATP-triggered aggregable DNA micelle functionalized with mitochondrial-targeting and protein expression inhibition. The first PTT enhancement was achieved through adenosine triphosphate (ATP) induced hybridization chain reaction between micelles, which lead to the micelle aggregation and improve the local heating effect. Secondly, the mitochondrial-targeting triphenylphosphine (TPP) integrated on the DNA micelles further improve the PTT by dint of the mitochondrial sensitivity to heat. Thirdly, the thermal resistance of tumor cells was suppressed through the down-regulation of heat shock protein 70 under small interfering RNA. Through the coalition of ATP-responsive aggregation, mitochondrial-targeting and thermal resistance inhibition, this triple-enhanced PTT strategy offers a versatile platform for the precise and potent treatment of tumors, thereby advancing the clinical translation of photothermal therapy and stimuli-responsive nanomedicine.