C176-loaded and phosphatidylserine-modified nanoparticles treat retinal neovascularization by promoting M2 macrophage polarization

• Published in: Bioactive materials Vol. 39; pp. 392 - 405
• Main Authors: Shao, An, Jin, Lulu, Ge, Yanni, Ye, Ziqiang, Xu, Mingyu, Zhou, Yifan, Li, Yingyu, Wang, Linyan, Xu, Pinglong, Jin, Kai, Mao, Zhengwei, Ye, Juan
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.09.2024; KeAi Publishing Communications Ltd; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Angiogenesis; Animal models; Cell culture; cGAS-STING pathway; Cytokines; Dosage; Drug dosages; Electron microscopes; Inflammation; Inflammatory diseases; Macrophage polarization; Macrophages; Nanocarrier; Nanoparticles; Phenotypes; Phosphatidylserine; Polarization; Polyethylene glycol; Retina; Retinal detachment; Retinal neovascularization; Retinopathy; Vascular endothelial growth factor; Vascularization; United States > US; China; Japan; Nanocarrier; Retinal neovascularization; Macrophage polarization; cGAS-STING pathway
• ISSN: 2452-199X; 2097-1192; 2452-199X
• DOI: 10.1016/j.bioactmat.2024.05.038

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. •We synthesized intravitreally injectable phosphatidylserine-modified nanoparticles loaded with STING antagonist (PS@DMSN-C176).•PS@DMSN-C176 induce macrophage polarization to anti-inflammatory M2 phenotype by inhibiting STING.•PS@DMSN-C176 alleviates retinal neovascularization via macrophage-specific enhanced inhibition of retinal cGAS-STING signaling pathway.