DNA Nanoflower LYTACs Enable Efficient VEGF Degradation and Verteporfin Loading for Combined Therapy of Wet Age‐Related Macular Degeneration

Wet age-related macular degeneration (wAMD), characterized by pathological choroidal neovascularization (CNV), is a leading cause of irreversible vision loss in the elderly. The current standard treatment-anti-vascular endothelial growth factor (VEGF) therapy-effectively manages neovascularization in many patients. However, some experience suboptimal responses, and frequent intravitreal injections raise safety concerns. Photodynamic therapy is another effective option for treating wAMD, but it can lead to an increase in reactive VEGF after the procedure, resulting in CNV recurrence. In response to these challenges, we propose an integrated approach that combines a DNA nanoflower VEGF degrader with photodynamic therapy. The DNA nanoflower consists of numerous aptamer-based lysosome-targeted chimaera (LYTAC) units, which drive extracellular VEGF in the lesion area to the lysosome for degradation. Simultaneously, the DNA nanoflower acts as a carrier for verteporfin (VER), a clinically used photosensitizer. The resulting nanoflower, named NF@VER, generates reactive oxygen species under near-infrared light to induce endothelial cell death. These combined effects on endothelial cells effectively block VEGF-induced CNV in vivo, without causing noticeable side effects. Overall, this innovative approach presents a precise and effective strategy for treating wAMD, reducing the risk of VEGF reactivation-induced CNV recurrence, and minimizing the systemic side effects associated with photodynamic therapy.