Abstract：
Monotherapy, especially the use of antibodies targeting vascular endothelial growth factor (VEGF), has shown limitations in treating choroidal neovascularization (CNV) since reactive oxygen species (ROS) also exacerbate CNV formation. Herein, we developed a combination therapy based on a DNA origami platform targeting multiple components of ocular neovascularization. Our study demonstrated that ocular neovascularization was markedly suppressed by intravitreal injection of a rectangular DNA origami sheet modified with VEGF aptamers (Ap) conjugated to an anti-VEGF antibody (aV) via matrix metalloproteinase (MMP)-cleavable peptide linkers in a mouse model of CNV. Typically, the DNA origami-based therapeutic platform selectively accumulates in neovascularization lesions owing to the dual-targeting ability of the aV and Ap, followed by the cleavage of the peptide linker by MMPs to release the antibody. Together, the released antibody and Ap inhibited VEGF activity. Moreover, the residual bare DNA origami could effectively scavenge ROS, reducing oxidative stress at CNV sites and thus maximizing the synergistic effects of inhibiting neovascularization.
摘要：
单一疗法,特别是使用针对血管内皮生长因子（VEGF）的抗体，在治疗脉络膜新生血管(CNV)方面显示出局限性,因为活性氧(ROS)也会加剧CNV的形成。在这里，我们开发了一种基于DNA折纸平台的联合疗法,该平台靶向眼部新生血管的多种成分.我们的研究表明，在小鼠模型中，玻璃体内注射通过基质金属蛋白酶（MMP）可裂解的肽接头与抗VEGF抗体（aV）缀合的VEGF适体（Ap）修饰的矩形DNA折纸片可显着抑制眼部新生血管形成。通常,由于aV和Ap的双重靶向能力，基于DNA折纸的治疗平台选择性地积累在新生血管病变中，然后通过MMP切割肽接头以释放抗体。一起,释放的抗体和Ap抑制VEGF活性。此外，剩余的裸DNA折纸可以有效清除ROS，减少CNV位点的氧化应激，从而最大限度地发挥抑制新生血管的协同作用。
