An Integrated DNA Origami-Based RNA Degrader for Targeted Degradation of Oncogenic Mutant KRAS mRNA

Abstract

Targeting mutant KRAS represents a critical yet unmet therapeutic challenge across multiple malignancies, as the structural diversity of oncogenic variants and absence of druggable pockets have impeded the development of effective small-molecule inhibitors. Here, we report an integrated RNA degrader system constructed on a six-helix bundle DNA origami (6HB) scaffold that enables efficient and targeted degradation of mutant KRAS mRNA. The system coassembles two modular functional units: an enzyme activity control module comprising an engineered barnase variant and a programmable recognition strand for direct, endogenous-machinery-independent RNA cleavage, and a cell-penetrating module featuring TAT peptides for cytosolic delivery. This integrated architecture eliminates spatiotemporal barriers between delivery and catalysis, achieving robust KRAS mRNA degradation within 16 h while maintaining sufficient specificity for mutant transcripts with minimal impact on wild-type forms. This study demonstrates a proof-of-concept nanoscale platform that integrates targeting, delivery, and catalytic functions for RNA degradation.