An in vitro-transcribed circular RNA targets the mitochondrial inner membrane cardiolipin to ablate EIF4G2 + /PTBP1 + pan-adenocarcinoma.
Zunyong FengXuanbo ZhangJing ZhouQiang LiLiuxi ChuGuangfu DiZhengyuan XuQun ChenMing WangXiaochun JiangHongping XiaXiaoyuan Shawn ChenPublished in: Nature cancer (2023)
In vitro-transcribed (IVT) mRNA has arisen as a rapid method for the production of nucleic acid drugs. Here, we have constructed an oncolytic IVT mRNA that utilizes human rhinovirus type 2 (HRV2) internal ribosomal entry sites (IRESs) to selectively trigger translation in cancer cells with high expression of EIF4G2 and PTBP1. The oncolytic effect was provided by a long hGSDMD c .825 T>A/c.884 A>G -F1L CT mutant mRNA sequence with mitochondrial inner membrane cardiolipin targeting toxicity that triggers mitophagy. Utilizing the permuted intron-exon (PIE) splicing circularization strategy and lipid nanoparticle (LNP) encapsulation reduced immunogenicity of the mRNA and enabled delivery to eukaryotic cells in vivo. Engineered HRV2 IRESs-GSDMD p.D275E/E295G -F1L CT circRNA-LNPs (GSDMD ENG circRNA) successfully inhibited EIF4G2 + /PTBP1 + pan-adenocarcinoma xenografts growth. Importantly, in a spontaneous tumor model with abnormal EIF4G2 and PTBP1 caused by KRAS G12D mutation, GSDMD ENG circRNA significantly prevented the occurrence of pancreatic, lung and colon adenocarcinoma, improved the survival rate and induced persistent KRAS G12D tumor antigen-specific cytotoxic T lymphocyte responses.
Keyphrases
- binding protein
- nucleic acid
- oxidative stress
- squamous cell carcinoma
- wild type
- computed tomography
- induced apoptosis
- endothelial cells
- image quality
- locally advanced
- dual energy
- risk assessment
- poor prognosis
- diabetic rats
- high glucose
- drug induced
- positron emission tomography
- cancer therapy
- radiation therapy
- cell cycle arrest
- signaling pathway
- cell death
- cell proliferation
- free survival
- induced pluripotent stem cells
- pluripotent stem cells
- quantum dots
- pi k akt
- anti inflammatory
- sensitive detection