Zuo Jiayi, Pan Yining, Wang Yuanli, Wang Wei, Zhang Haojie, Zhang Si, Wu Youru, Chen Jiangfan, Yao Qingqing
State Key Laboratory of Eye Health, Optometry and Vision Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
Mater Today Bio. 2025 Apr 10;32:101757. doi: 10.1016/j.mtbio.2025.101757. eCollection 2025 Jun.
Neovascular age-related macular degeneration (nAMD) has become the leading cause of vision loss in people over 60 years old. Anti-vascular endothelial growth factor (anti-VEGF), the current first-line drug for the treatment of nAMD, suffers from poor patient compliance and fundus fibrosis scar formation. In addition to VEGF, oxidative stress and inflammation also play key roles in the pathological process of choroidal neovascularization (CNV). Therefore, combinational therapeutics with anti-angiogenic, reactive oxygen species (ROS)-scavenging and anti-inflammatory functions will broaden therapeutic effects and reduce side effects. The Yes-associated protein-1 (YAP) has proven to inhibit angiogenesis, inflammation, and subretinal fibrosis in CNV. Herein, verteporfin (VP), the inhibitor of YAP, was encapsulated into a polydopamine modified mesoporous silica nanoparticle (PMSN-VP NPs) and then conjugated with PLGA-PEG-PBA decorated cerium oxide nanoparticles (PPCeO NPs) to develop an integrated nano-drug delivery system. The PMSN-VP@PPCeO NPs exhibited ROS-responsive degradation and VP release behaviors, and our data revealed that the PMSN-VP@PPCeO NPs downregulated angiogenic-related and fibrosis-related gene expressions in human umbilical vein endothelial cells (HUVECs) and further showed excellent anti-oxidative and anti-inflammatory capacities in BV2 cells. More importantly, the PMSN-VP@PPCeO NPs significantly suppressed vascular leakage and macrophage infiltration in the laser-induced CNV lesions of mice. Overall, our findings demonstrated that the PMSN-VP@PPCeO NPs provided an effective therapeutic strategy for nAMD.
新生血管性年龄相关性黄斑变性（nAMD）已成为60岁以上人群视力丧失的主要原因。抗血管内皮生长因子（抗VEGF）是目前治疗nAMD的一线药物，但存在患者依从性差和眼底纤维化瘢痕形成的问题。除VEGF外，氧化应激和炎症在脉络膜新生血管（CNV）的病理过程中也起关键作用。因此，具有抗血管生成、清除活性氧（ROS）和抗炎功能的联合疗法将拓宽治疗效果并减少副作用。Yes相关蛋白1（YAP）已被证明可抑制CNV中的血管生成、炎症和视网膜下纤维化。在此，将YAP抑制剂维替泊芬（VP）封装到聚多巴胺修饰的介孔二氧化硅纳米颗粒（PMSN-VP NPs）中，然后与聚乳酸-羟基乙酸共聚物-聚乙二醇-苯硼酸修饰的氧化铈纳米颗粒（PPCeO NPs）偶联，开发出一种集成纳米药物递送系统。PMSN-VP@PPCeO NPs表现出ROS响应性降解和VP释放行为，我们的数据显示，PMSN-VP@PPCeO NPs下调了人脐静脉内皮细胞（HUVECs）中血管生成相关和纤维化相关基因的表达，并在BV2细胞中进一步显示出优异的抗氧化和抗炎能力。更重要的是，PMSN-VP@PPCeO NPs显著抑制了小鼠激光诱导的CNV病变中的血管渗漏和巨噬细胞浸润。总体而言，我们的研究结果表明，PMSN-VP@PPCeO NPs为nAMD提供了一种有效的治疗策略。
