Oral GSDMD‐N mRNA Nanoparticle‐Induced Pyroptosis for the Treatment of Colorectal Cancer

The pathogenesis of colorectal cancer (CRC) is complicated, as evidenced by the intensive crosstalk between cancer cells and the gut microbiota. The inflammatory microenvironment surrounding cancer cells accelerates the reproduction of pathogenic bacteria, and the polyketide synthase-catalyzed metabolites generated by these bacteria correspondingly promote cancer cell proliferation, thus forming a detrimental cancer-bacteria cycle. Here, we demonstrated that gasdermin-D (GSDMD) (the executive protein of cell pyroptosis) improves gut dysbiosis in an obese mouse model, whereas GSDMD deficiency promotes CRC development in these mice, thus suggesting that GSDMD is a potential target for CRC therapy. In this study, we designed a novel dual-targeted GSH-sensitive nanodrug delivery system aimed at specifically delivering mRNA encoding the N-terminal domain of GSDMD (GSDMD-N mRNA) to local CRC tissues. Such a system helps to induce pyroptosis in CRC cells and corrects gut dysbiosis caused by the tumor microenvironment, thus achieving a dual regulatory effect. This study contributes to the current understanding of the pathophysiological functions of GSDMD-mediated pyroptosis in CRC and suggests a new strategy for precise CRC therapy targeting GSDMD, thereby providing a solid theoretical basis and experimental evidence for the development of mRNA nanodrug delivery systems.