Mitochondria-Mediated HSP Inhibition Strategy for Enhanced Low-Temperature Photothermal Therapy

Low-temperature photothermal therapy (PTT) has the advantageofcausing less damage to normal tissues and has attracted great attentionin recent years. However, the efficacy of low-temperature PTT is restrictedby the overexpression of heat shock proteins (HSPs), specificallyHSP70 and HSP90. Inhibiting the function of these HSPs is a majorstrategy used in the development of new cancer therapies. Herein,we designed four T780T-containing thermosensitive nanoparticles tointerrupt the energy supply for HSP expression using their TPP-basedmitochondrial targeting action. The reversal behavior of the nanoparticleson the gambogic acid (GA)-induced compensatory increase of HSP70 wasinvestigated in vitro by Western blot and in vivo by immunohistochemistry. The in vivo anticancer efficacy of the low-temperature PTT based on these thermosensitivenanoparticles was also systematically examined. The design proposesfor the first time to utilize and elucidate the mechanism of the mitochondrialtargeting of T780T-containing NPs in synergy with the HSP90 inhibitionof GA to achieve an effective low-temperature PTT. This work not onlyprovides a novel pathway for the dual inhibition of HSP70 and HSP90but also opens up a new approach for low-temperature PTT of tumors.