Microenvironment-responsive tetrahedral DNA nanoplatform for specific and enhanced tumor therapy through differential ROS and angiogenesis modulation

Achieving spatiotemporally differential regulation of therapeutic activity between tumors and normal tissues remaines a paramount challenge in precision nanomedicine. To address this challenge, an intelligent nanostructure is engineered by assembling the DNAzyme-integrated tetrahedral DNA (TDN) and pyropheophorbide-a (PPa) on MnO nanoparticles (NPs), which is abbreviated as TDN-MPs. Specifically, TDN-MPs generate reactive oxygen species (ROS) under laser irradiation and exhibit excellent photodynamic therapy (PDT) activity to kill tumor cells. The Mn²⁺ ions released from TDN-MPs triggered by tumor microenvironment (TME) alter the geometric structure of TDN and release the activated DNAzyme for cleaving vascular endothelial growth factor receptor 2 (VEGFR2) mRNA, which inhibits the formation of new blood vessels at tumor site. Conversely, the structurally complete TDN-MPs in physiological environment not only maintain DNAzyme in a silent state but also act antioxidants to eliminate ROS, which enables the goal of reducing toxic effects of DNAzyme and ROS toward normal sites. This strategy takes advantage of the geometric variability of TDN to differentially regulate ROS and VEGFR2 levels between tumor and normal tissues, significantly enhancing the therapeutic effect while minimizing systemic toxicity. This study presents a robust approach for achieving high-specificity tumor therapy through the rational design of intelligent DNA-based nanostructures.