Exosome-mediated delivery of an anti-angiogenic peptide inhibits pathological retinal angiogenesis.
Exosome-mediated delivery of an anti-angiogenic peptide inhibits pathological retinal angiogenesis.
复制标题
外泌体介导的抗血管生成肽的递送抑制病理性视网膜血管生成
作者：
Dong X;Lei Y;Yu Z;Wang T;Liu Y;Han G;Zhang X;Li Y;Song Y;Xu H;Du M;Yin H;Wang X;Yan H
背景：病理性血管生成是许多视力威胁疾病的标志。抗vegf是一种具有显著有益效果的主要治疗方法。然而，这类药物需要经常在玻璃体内注射。我们之前的工作建立了一种有效修饰外泌体（EXOs）以装载治疗肽的方法。在这里，我们使用该系统加载抗血管生成肽KV11，旨在建立一种基于exo的治疗策略来抑制视网膜新生血管的形成。方法：利用锚定肽CP05，我们将KV11连接到内皮细胞（EC）衍生的exo，得到EXOKV11。我们通过眼眶后注射和玻璃体内注射两种常用的眼部注射方法来测试EXOKV11的递送效率。通过氧诱导视网膜病变（OIR）模型和VEGF注射模型，我们测试了EXOKV11对新血管形成、EC增殖和血管通透性的影响。体外实验验证其作用机制，分析EXOKV11对EC增殖、迁移和发芽的影响。结果：通过EXO加载系统，KV11能更有效地通过眶后注射进入小鼠视网膜血管。在OIR模型和VEGF注射模型中，EXOKV11均比单独使用KV11更有效地抑制新生血管和血管渗漏。眼眶后注射EXOKV11的治疗效果与玻璃体内注射VEGF-trap相当。在机制上，KV11单独抑制vegf下游信号，而EXOKV11表现出更强的作用。结论：我们使用exo作为KV11眼内传递的载体。我们发现KV11本身通过眶后注射具有抗血管生成作用，但当与exo一起递送时，这种作用大大增强。因此，该系统具有通过眶后注射治疗增殖性视网膜病变的潜力，与玻璃体内注射相比，其侵入性更小。
Background: Pathological angiogenesis is the hallmark of many vision-threatening diseases. Anti-VEGF is a primary treatment with substantial beneficial effects. However, such agents require frequent intravitreal injections. Our previous work established a method for effectively modifying exosomes (EXOs) for loading therapeutic peptides. Here, we used this system to load the anti-angiogenic peptide KV11, aiming to establish an EXO-based therapy strategy to suppress neovascularization in the retina. Methods: Using an anchoring peptide, CP05, we linked KV11 to endothelial cell (EC) derived EXOs, yielding EXOKV11. We tested the delivery efficiency of EXOKV11 via two commonly used ocular injection methods: retro-orbital injection and intravitreal injection. Deploying an oxygen-induced retinopathy (OIR) model and a VEGF injection model, we tested the effects of EXOKV11 on neovascular formation, EC proliferation, and vascular permeability. In vitro experiments were used to test the mechanism and to analyze the effects of EXOKV11 on EC proliferation, migration, and sprouting. Results: By using the EXO loading system, KV11 was more efficiently delivered to the blood vessels of the mouse retina via retro-orbital injection. In both OIR model and VEGF injection model, EXOKV11 was more effective than KV11 alone in inhibiting neovascularization and vessel leakage. The therapeutic effect of retro-orbital injection of EXOKV11 was comparable to the intravitreal injection of VEGF-trap. Mechanistically, KV11 alone inhibited VEGF-downstream signaling, while EXOKV11 showed a stronger effect. Conclusions: We used EXOs as a carrier for intraocular delivery of KV11. We showed that KV11 itself has an anti-angiogenic effect through retro-orbital injection, but that this effect was greatly enhanced when delivered with EXOs. Thus, this system has the potential to treat proliferative retinopathy via retro-orbital injection which is a less invasive manner compared with intravitreal injection.