DNA-Assisted Smart Nanocarriers: Progress, Challenges, and Opportunities.

Due to powerful breakthroughs in nanotechnology, smart delivery mechanisms have rapidly emerged for use in diverse applications across biomedical research and therapeutic development. Recent efforts toward understanding stimuli-responsive strategies have led to substantial improvements in their conceptual application and in vitro efficiency. Because disease targets for therapy are often localized in specific cells, organs, or tissues, an enhanced permeability and retention (EPR)-based strategy remains inadequate for accurate drug delivery and release to target regions, resulting in an insufficient drug concentration reaching the target region and undesired side effects. To address these issues, more precise and remote-controlled stimuli-responsive systems, which recognize and react to changes in the pathophysiological microenvironment, were recently elucidated as feasible on-demand drug-delivery systems. In this Perspective, we focus on progress toward stimuli-responsive drug-delivery systems that utilize dynamic DNA molecules by exploiting DNA nanotechnology. DNA structures can be precisely reconfigured by external and internal stimuli to drive the release of a loaded drug in a target region with appropriate microenvironments. We describe the chemical, physical, and biological engineering principles and strategies for constructing DNA-assisted nanocarriers. We also provide a summary of smart nanocarrier systems, organized with respect to the structural changes in the DNA strand in the microenvironment, resulting from changes in pH and temperature and the presence of intracellular oligonucleotides. To do so, we highlight recent advances in related biomedical research and applications as well as discuss major challenges and opportunities for DNA-assisted nanocarriers to guide the development of future in vivo therapies and clinical translation strategies.