Low-temperature photothermal therapy (PTT) has the advantage of causing less damage to normal tissues and has attracted great attention in recent years. However, the efficacy of low-temperature PTT is restricted by the overexpression of heat shock proteins (HSPs), specifically HSP70 and HSP90. Inhibiting the function of these HSPs is a major strategy used in the development of new cancer therapies. Herein, we designed four T780T-containing thermosensitive nanoparticles to interrupt the energy supply for HSP expression using their TPPbased mitochondrial targeting action. The reversal behavior of the nanoparticles on the gambogic acid (GA)-induced compensatory increase of HSP70 was investigated in vitro by Western blot and in vivo by immunohistochemistry. The in vivo anticancer efficacy of the low-temperature PTT based on these thermosensitive nanoparticles was also systematically examined. The design proposes for the first time to utilize and elucidate the mechanism of the mitochondrial targeting of T780T-containing NPs in synergy with the HSP90 inhibition of GA to achieve an effective low-temperature PTT. This work not only provides a novel pathway for the dual inhibition of HSP70 and HSP90 but also opens up a new approach for low-temperature PTT of tumors.

Recently, nanoformulations have been widely applied in the delivery of organic photothermal agents (OPTAs) for cancer therapy to prolong blood circulation or improve tumor-targeting capacity. However, the systematic evaluations of their effects on the photothermal behavior of OPTAs are limited, especially for different types of nanoparticle systems. Herein, we prepared two kinds of nanoparticles (BSA and PEG nanoparticles (NPs)) to load an OPTA, a cyanine photosensitizer (IR780-O-TPE), and investigated their photothermal response, organelle targeting, and in vivo therapeutic efficacy. Due to different assembly forms, the two NPs showed distinct morphological changes after exposure to laser or hyperthermia. Under laser irradiation at 808 nm, BSA NPs could release IR780-O-TPE more efficiently than PEG NPs. We speculate that this phenomenon is probably caused by dual-responsive release of IR780-O-TPE from BSA NPs against light and hyperthermia. Moreover, IR780-O-TPE/BSA NPs were highly mitochondria-targeting and therefore displayed significant inhibition of cell viability. In contrast, IR780-O-TPE/PEG NPs were “shell–core” nanostructures and more stable under laser stimulation. As a consequence, the mitochondria-targeting and anticancer photothermal therapy by IR780-O-TPE/PEG NPs was less obvious. This study revealed the significance of nanocarrier design for OPTA delivery and demonstrated that BSA NPs could release IR780-O-TPE more effectively for efficient photothermal therapy. We also believe that the dual-responsive release of OPTAs from NPs can provide an effective strategy to promote anticancer photothermal treatment.