Direct Cytosolic Delivery of siRNA Conjugates: A Paradigm in Antiangiogenic Therapy for Choroidal Neovascularization

作者：Tongqi Li, Yue Wang, Xiyi Chen, Hongyan Cui, Liuwei Zhang, Jun Liu, Jin Wang, Jin Wang, Xiumei Wang, Yan Zhao, Qixian Chen, Jing Wang, Jing Wang · 发表于：ACS Nano · 年份：2025 · DOI：10.1021/acsnano.4c18924 · 被引用次数：11 · 研究领域：RNA Interference and Gene Delivery、MicroRNA in disease regulation、Extracellular vesicles in disease

Small interfering RNA (siRNA) has garnered tremendous interest as a potential therapeutic tool because of its intriguing gene-silencing ability. Toward the success in the manufacture of siRNA therapeutics for the potential treatment of choroidal neovascularization (CNV), siRNA conjugated with dual functional units of membrane-penetrating heptafluoropropyl and age-related macular degeneration-targeting cyclic Arg-Gly-Asp (RGD) peptide was attempted for transcellular transportation into the cell interiors. Of note, cyclic RGD allowed selective affinities toward the angiogenic endothelial cells in the pathological CNV. Noteworthy is the functional heptafluoropropyl group, due to its tempting lipophobic and hydrophobic properties, stimulating energy-independent transcellular trafficking behaviors to the cytoplasm directly from the extracellular compartments, namely, the nonendocytotic pathway. The behaviors manage to avoid the well-acknowledged drawback of endolysosomal entrapment, which is deemed to be the critical threat to the biovulnerable genomic therapeutics, thereby contributing to potent gene knockdown at the affected cells. Aiming for treatment of CNV, the siRNA duo was schemed with appropriate chemistry-based modifications for the targeted knockdown of both angiogenic VEGF-A and VEGF-R2. Subsequent investigations verified the potent reduction of vascular leakage, and our proposed siRNA duo accomplished a significant reduction of 67.3% in the mean area of the CNV lesion....