Tumor-Specific RNA Editing Nanomedicine Activated by Wnt Signaling for Methionine Metabolic Immunotherapy

Tumor cells often outcompete T cells for methionine, impairing T cell function and immune surveillance. However, selectively targeting methionine metabolism in tumors remains challenging. Here, we develop a Wnt-activated RNA editing nanoplatform (TREND) to specifically disrupt the tumor methionine transporter SLC43A2 and reprogram the metabolic competition between tumor cells and CD8+ T cells. By taking advantages of aberrant Wnt signaling pathway in tumor cells, we first established a Wnt-responsive promoter which was used to control the transcription of the plasmid encoding RNA editor (CasRx) targeting SLC43A2, in order to ensure RNA editing in tumor cells with activated Wnt signaling. To further promote the accumulation and the intracellular translocation of CasRx in the tumor cells in vivo, a tumor-targeted delivery system was engineered by cloaking hybrid cell membrane over the polymeric carriers for the systemic delivery of CasRx plasmid. Such a therapeutic strategy combining tumor-targeted delivery and tumor-specific RNA editing greatly relieves the metabolic competition of methionine between tumor cells and T cells, restores H3K79me2 and STAT5 expression and increases intracellular glutathione (GSH) to suppress ROS-driven activation of the NFAT/NR4a/Tox exhaustion axis, thereby reducing immune checkpoint expression. This strategy significantly boosts the activity of T-cell effectors and suppresses the progression of tumors in multiple mouse models, providing a modular and programmable RNA-based approach for tumor-targeted metabolic immunotherapy.