DNA-Based nanostructures for tumor microenvironment-responsive drug delivery

DNA nanostructures, with sequence programmability, biocompatibility, and structural versatility, have emerged as promising tools for biomedical applications, particularly in targeted drug delivery and therapeutic interventions. The tumor microenvironment (TME) is characterized by dysregulated pH gradients, elevated glutathione (GSH), hypoxia, adenosine triphosphate (ATP) abundance, and aberrant enzymatic activity, presenting significant challenges for conventional therapies. DNA-based nanostructure enables precise control over drug-loading efficiency, tumor-targeted specificity, and spatiotemporal release mechanisms, making them ideal for tumor-targeted drug delivery. In this review, we highlight recent advances in versatile TME-responsive DNA-based nanostructures for precise therapeutic drug delivery. First, we discuss the fundamental design principles governing the structural configuration and functional integration of DNA nanostructures in TME-responsive drug delivery. Next, we summarize the mechanisms by which TME characteristics, including pH gradients, glutathione (GSH), adenosine triphosphate (ATP), enzymatic activity, and multiple stimuli, regulate the targeting and controlled release of therapeutic payloads in DNA-based nanostructures. Finally, this review provides an outlook on future research directions aimed at further optimizing the designability of DNA nanostructure-based drug delivery systems, underscoring the necessity of interdisciplinary collaboration. It is expected that these principles facilitate the future development of next-generation DNA nanostructure-based drugs with smart, precise, safe, and potent therapeutic capabilities.