Enzyme-Responsive\nDNA Origami-Antibody Conjugates\nfor Targeted and Combined Therapy of Choroidal Neovascularization

Monotherapy, especially the use of antibodies targeting\nvascular\nendothelial growth factor (VEGF), has shown limitations in treating\nchoroidal neovascularization (CNV) since reactive oxygen species (ROS)\nalso exacerbate CNV formation. Herein, we developed a combination\ntherapy based on a DNA origami platform targeting multiple components\nof ocular neovascularization. Our study demonstrated that ocular neovascularization\nwas markedly suppressed by intravitreal injection of a rectangular\nDNA origami sheet modified with VEGF aptamers (Ap) conjugated to an\nanti-VEGF antibody (aV) via matrix metalloproteinase (MMP)-cleavable\npeptide linkers in a mouse model of CNV. Typically, the DNA origami-based\ntherapeutic platform selectively accumulates in neovascularization\nlesions owing to the dual-targeting ability of the aV and Ap, followed\nby the cleavage of the peptide linker by MMPs to release the antibody.\nTogether, the released antibody and Ap inhibited VEGF activity. Moreover,\nthe residual bare DNA origami could effectively scavenge ROS, reducing\noxidative stress at CNV sites and thus maximizing the synergistic\neffects of inhibiting neovascularization.