PDF(Pubmed)
Abstract：
Retinal neovascularization (RNV), a typical pathological manifestation involved in most neovascular diseases, causes retinal detachment, vision loss, and ultimately irreversible blindness. Repeated intravitreal injections of anti-VEGF drugs were developed against RNV, with limitations of incomplete responses and adverse effects. Therefore, a new treatment with a better curative effect and more prolonged dosage is demanding. Here, we induced macrophage polarization to anti-inflammatory M2 phenotype by inhibiting cGAS-STING signaling with an antagonist C176, appreciating the role of cGAS-STING signaling in the retina in pro-inflammatory M1 polarization. C176-loaded and phosphatidylserine-modified dendritic mesoporous silica nanoparticles were constructed and examined by a single intravitreal injection. The biosafe nanoparticles were phagocytosed by retinal macrophages through a phosphatidylserine-mediated \"eat me\" signal, which persistently release C176 to suppress STING signaling and thereby promote macrophage M2 polarization specifically. A single dosage can effectively alleviate pathological angiogenesis phenotypes in murine oxygen-induced retinopathy models. In conclusion, these C176-loaded nanoparticles with enhanced cell uptake and long-lasting STING inhibition effects might serve as a promising way for treating RNV.
摘要：
视网膜新生血管(RNV),大多数新生血管性疾病的典型病理表现，导致视网膜脱离,视力丧失,最终不可逆转的失明。针对RNV开发了抗VEGF药物的重复玻璃体内注射，具有不完全反应和不利影响的局限性。因此,需要一种疗效更好、剂量更长的新疗法。这里,我们通过用拮抗剂C176抑制cGAS-STING信号诱导巨噬细胞极化为抗炎M2表型,从而了解cGAS-STING信号在视网膜中在促炎M1极化中的作用.C176负载和磷脂酰丝氨酸修饰的树枝状介孔二氧化硅纳米颗粒通过单次玻璃体内注射构建和检查。生物安全的纳米颗粒被视网膜巨噬细胞通过磷脂酰丝氨酸介导的“吃我”信号吞噬，持续释放C176以抑制STING信号传导，从而特异性促进巨噬细胞M2极化。单一剂量可有效缓解小鼠氧诱导视网膜病变模型中的病理性血管生成表型。总之,这些C176负载的纳米颗粒具有增强的细胞摄取和持久的STING抑制作用，可能是治疗RNV的有希望的方法。
