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.