Chemical modifications to enhance the stability of DNA nanoparticles for biological applications

Synthetic DNA nanoparticles offer unique modularity and chemical versatility to build systems for biomedical applications. Extensive research into DNA nanoparticles has led to superior control over loading therapeutic cargo, adding targeting and imaging moieties, and designing desired geometries. One of the main barriers to translating DNA nanoparticles into clinical therapies, however, is their stability in biological environments. Introduction of DNA nanoparticles in biological environments exposes them to various stressors such as nuclease enzymes, depleted salt conditions, and alterations in oxidizing conditions. It is therefore necessary to develop strategies to protect DNA nanoparticles against such stressors to preserve their structural integrity and function. In this review, we highlight dominant chemical modifications that have been optimized to secure DNA nanoparticles against stressors with a focus on biological applications. We provide comprehensive accounts of notable examples from recent results and discuss aspects of DNA nanoparticle stability that require the community's attention.