A mitochondria targeted cascade reaction nanosystem for improved therapeutic effect by overcoming cellular resistance

Mitigating cellular resistance, which could enhance the sensitivity of tumor cells to treatment, is a promising approach for obtaining better therapeutic outcomes. However, the present designs of materials generally disregard this point, or only focus on a single specific resistance. Herein, a strategy based on a series of cascade reactions aiming to suppress multiple cellular resistances is designed by integrating photothermal and chemotherapy into a mitochondria targeted nanosystem (AuBPs@TD). The intelligent nanosystem is fabricated by modifying gold nanobipyramids (AuBPs) with triphenylphosphonium (TPP) functionalized dichloroacetic acid (DCA). TPP serves as a "navigation system" and facilitates the location of AuBPs@TD in the mitochondria. Moreover, the released DCA promoted by the photothermal effect of AuBPs, as the mitochondrial kinase inhibitor, could inhibit glycolysis, and lead to a repressed expression of heat shock protein 90, which is the main resistance protein in cancer cells against photothermal therapy (PTT). Thus, the photothermal antitumor effect can be significantly improved. For the other cascade passage, the hyperthermal atmosphere depresses the expression of P-glycoprotein, a protein associated with drug resistance, and consequently prevents DCA molecules from being expelled in return. Furthermore, the retained DCA molecules elevate the concentration of intracellular hydrogen peroxide, and due to the peroxidase-like activity of AuBPs, increased intracellular reactive oxygen species could be obtained to accelerate apoptosis. As a result, these cascade reactions lead to significant inhibition of cellular resistance and greatly improve the therapeutic performance. This work paves a new way for suppressing cellular resistance to achieve the desired therapeutic effect.