In vivo translation of DNA origami: a virus-like particle design framework.

DNA origami nanostructures are self-assembling nanostructures being developed as vaccines, therapeutics, and drug delivery systems. Despite impressive advances, physiological barriers have limited their clinical translation. This review proposes a DNA virus-like particle framework to engineer DNA origami nanostructures that overcome these barriers. It maps DNA origami designs onto three interlinked modules-genome, envelope, and spike-mirroring the organizational logic of viruses. Through this lens, we highlight four priorities for translation: (i) expanding the envelope and spike toolkit to match genome design, (ii) establishing combinatorial libraries to map how module interactions govern biological behavior, (iii) mining library datasets computationally to build predictive models, and (iv) exploring adaptive architectures for multibarrier crossing. Together, this framework charts a path toward translation-ready DNA nanodevices.