A Metal-Phenolic Nanocoordinator Launches Radiotherapeutic Cancer Pyroptosis Through an Epigenetic Mechanism

摘要

Radiotherapy, although clinically effective in immunoactivation, still cannotradio-functionalize tumor as a potent immunogenetic center. Given thatnewly found pyroptosis efficiently releases immunogenic damage-associatedmolecular patterns, initiating radiotherapeutic pyroptosis may turn a vision ofradiotherapy-induced immunity into reality. However, a precondition is thatthe absent gasdermin E (GSDME), which essentiates in caspase-3-mediatedpyroptosis, can be well translated in cancer cells. Here, an epigenetic strategyto launch cancer pyroptosis in radiotherapy is introduced. The nanocoordinator(PWE) is constructed via a metal–phenolic coordination between polyphenolicDNA methyltransferase inhibitor (epigallocatechin-3-gallate, EGCG),high-Z radiosensitizer (W~(6+)), and polyphenol-modified block copolymer.While recovering GSDME expression by EGCG, PWE cleaves GSDME intofragmented GSDME N-terminal (pyroptotic key protein) via radiotherapeuticcaspase-3. To examine anti-tumor immune activities, PWE amplifiesimmunological effects of traditional radiotherapy and decreases radiotherapyupregulatedregulatory T cells, providing new insight into tumor radiotherapy.