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

• Published in: Advanced functional materials 2023-06, Vol.33 (23), p.n/a
• Main Authors: Wang, Guohao, Li, Bei, Tian, Hao, Xie, Lisi, Yan, Jie, Sang, Wei, Li, Jie, Zhang, Zhan, Li, Wenxi, Dai, Yunlu
• Format: Article
• Language: English
• Subjects: Block copolymers; Cancer; cancer immunotherapy; Damage patterns; DNA demethylation; Immunology; Lymphocytes; Materials science; metal–phenolic networks; pyroptosis; Radiation therapy; radiotherapy; Tumors
• ISSN: 1616-301X; 1616-3028
• DOI: 10.1002/adfm.202213425

Radiotherapy, although clinically effective in immunoactivation, still cannot radio‐functionalize tumor as a potent immunogenetic center. Given that newly found pyroptosis efficiently releases immunogenic damage‐associated molecular patterns, initiating radiotherapeutic pyroptosis may turn a vision of radiotherapy‐induced immunity into reality. However, a precondition is that the absent gasdermin E (GSDME), which essentiates in caspase‐3‐mediated pyroptosis, can be well translated in cancer cells. Here, an epigenetic strategy to launch cancer pyroptosis in radiotherapy is introduced. The nanocoordinator (PWE) is constructed via a metal–phenolic coordination between polyphenolic DNA methyltransferase inhibitor (epigallocatechin‐3‐gallate, EGCG), high‐Z radiosensitizer (W6+), and polyphenol‐modified block copolymer. While recovering GSDME expression by EGCG, PWE cleaves GSDME into fragmented GSDME N‐terminal (pyroptotic key protein) via radiotherapeutic caspase‐3. To examine anti‐tumor immune activities, PWE amplifies immunological effects of traditional radiotherapy and decreases radiotherapy‐upregulated regulatory T cells, providing new insight into tumor radiotherapy. A high‐Z radiosensitizer‐based metal–phenolic network is engineered to switch radiotherapeutic cell apoptosis to pyroptosis mode, broadening the applied scope of clinical radiotherapy into oncoimmunology. PWE nanoparticles upregulate the cellular gasdermin E (GSDME) expression through DNA demethylation. Meanwhile, X‐ray‐stimulated W6+‐sensitized radiotherapy activates the “Bax–Cytochrome c‐Caspase‐9–Caspase‐3” signaling pathway to cleave the GSDME, inducing pyroptosis. The radiotherapeutic pyroptosis evokes potent anti‐tumor immunoresponse and inhibits immune suppressors (e.g., M2 macrophages and regulatory T cells), regressing primary tumor, abscopal tumor, and even systemic metastasis efficiently.