An oncolytic circular RNA therapy for adenocarcinomas

A lipid nanoparticle (LNP)-delivered circular RNA that drives tumor-selective expression of the pore-forming protein GSDMD could help treat adenocarcinomas by inducing mitochondrial damage and immunogenic mitophagy and necroptosis in tumor cells.

An in vitro-transcribed circular RNA encoding GSDMD was engineered to express a human rhinovirus type 2 internal ribosomal entry (IRES) site to trigger translation in cells with high levels of the translational regulators EIF4G2 and PTBP1, which are overexpressed in multiple cancer types. The GSDMD construct was modified by the introduction of point mutations that limited its activation in the cytoplasm, and by the addition of a mitochondrial membrane-targeting vaccinia virus F1L protein, yielding a construct that induced mitochondrial membrane toxicity via the interaction between GSDMD and the mitochondrial membrane phosopholipid cardiolipin. ...