Engineering in vivo behavior of DNA nanostructures toward organ-targeted drug delivery

DNA nanostructures have emerged as programmable and biocompatible platforms for drug delivery, offering precise control over size, shape, and surface properties. Recent advances have demonstrated their potential for organ-targeted delivery by utilizing ligand conjugation, structural engineering, and modulation of protein corona composition. Despite their promise, key challenges remain in predicting organ specificity and ensuring structural stability in vivo. This review provides a comprehensive overview of DNA nanostructures that have demonstrated organ-specific drug delivery, with emphasis on biodistribution profiles, in vivo targeting strategies, and the influence of physicochemical and biological barriers. We also highlight recent insights into corona-assisted targeting and administration route-dependent distribution, outlining strategies to enhance translational potential. Finally, we discuss critical challenges and future directions for clinical application of DNA nanostructures as targeted nanocarriers.