A nanoplatform reshaping intracellular osmolarity and redox homeostasis against colorectal cancer

Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemoresistance remaining a major obstacle in CRC treatment. Sodium persulfate (Na2S2O8) is a novel agent capable of producing •SO4- and Na+ for chemodynamic therapy (CDT). This can induce pyroptosis and ferroptosis instead of conventional apoptosis in tumor cells. Meanwhile, IR780-iodide (IR780), as an excellent phototherapy agent, can generate hyperthermia and generate a large amount of reactive oxygen species (ROS) to synergize with the CDT of Na2S2O8, with potential to overcome chemoresistance in CRC. However, the low stability of Na2S2O8 and the poor solubility of IR780 limit their applications in the medical field. Accordingly, for the first time, D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), Na2S2O8 and IR780 were rationally designed in a cascade-amplifying nanoplatform (Na2S2O8-IR780 NPs) via a co-assembly strategy. Combining Na2S2O8 and IR780 in a nanoplatform improves the stability of Na2S2O8 and the solubility of IR780. As a result, the Na2S2O8-IR780 NPs exhibited excellent antitumor efficacy in CRC cell lines and five chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models. This photo-chemodynamic nanoplatform provides a brand-new paradigm by manipulating osmolarity and redox homeostasis to overcome chemo-resistance and holds great potential for the treatment of CRC.