Cascade-targeted intervention of the NLRP3 inflammasome and downstream angiogenesis by curcumin nanoparticles for ocular neovascularization therapy.

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2026-09-01 DOI:10.1002/ctm2.70846

Siyu Jiang, Ziwei Cheng, Yujuan Cai, Yanji Zhu, Nyamjargal Nyambayar, Ruijie Lin, Li Zhang, Jian Chen, Bing Xie, Xiuping Chen

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引用次数: 0

Abstract

Background: Retinal neovascularization (RNV) causes irreversible vision loss. Despite the benefits of anti-VEGF therapy, incomplete responses and persistent inflammation necessitate complementary treatments. Curcumin has anti-inflammatory and anti-angiogenic activity, but its poor solubility and bioavailability limit ocular application.

Methods: PLGA-encapsulated curcumin nanoparticles (Cur-NPs; approximately 125 nm) were produced using an ultrasound-microreactor platform. Therapeutic efficacy was assessed in oxygen-induced retinopathy (OIR) and Rho/VEGF transgenic mouse models following intravitreal administration. Neovascularization, vascular leakage, retinal structure, apoptosis, retinal distribution, and intraocular retention were evaluated using histology, fluorescence imaging, and longitudinal in vivo imaging. Mechanisms were investigated using single-cell transcriptomics, untargeted metabolomics, genetic loss-of-function, and pharmacological perturbation. Conbercept monotherapy and Cur-NP combination treatment were also evaluated.

Results: Cur-NPs reduced pathological neovascularization in both models and improved vascular integrity, decreased vascular leakage, preserved retinal architecture, and attenuated apoptosis in OIR mice. Compared with free curcumin, Cur-NPs showed broader retinal fluorescence distribution and prolonged intraocular fluorescence retention. Cur-NPs suppressed the NLRP3ASCCaspase-1 inflammasome and associated VEGF/VEGFR2 signaling. Genetic and pharmacological experiments supported a functional contribution of NLRP3 signaling to the anti-angiogenic effects of Cur-NPs. Multi-omics analyses revealed treatment-associated changes in retinal immune-cell states and metabolic pathways. ConberceptCur-NP combination therapy reduced neovascularization more than either treatment alone.

Conclusions: Cur-NPs inhibit pathological RNV through modulation of NLRP3-associated inflammatoryangiogenic signaling while improving retinal protection and intraocular retention. These findings support further evaluation of Cur-NPs as a potential upstream anti-inflammatory adjunct to VEGF-directed therapy.

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姜黄素纳米颗粒级联靶向干预NLRP3炎性体和下游血管生成用于眼部新生血管治疗。

背景：视网膜新生血管（RNV）导致不可逆的视力丧失。尽管抗vegf治疗有好处，但不完全反应和持续炎症需要补充治疗。姜黄素具有抗炎和抗血管生成活性，但其溶解度和生物利用度较差，限制了眼部应用。方法：利用超声微反应器平台制备plga包封的姜黄素纳米颗粒（curn - nps，约125 nm）。在玻璃体内给药后，对氧致视网膜病变（OIR）和Rho/VEGF转基因小鼠模型的治疗效果进行了评估。利用组织学、荧光成像和纵向体内成像评估新生血管、血管渗漏、视网膜结构、细胞凋亡、视网膜分布和眼内潴留。利用单细胞转录组学、非靶向代谢组学、遗传功能丧失和药理学扰动研究了其机制。对conberept单药治疗和Cur-NP联合治疗也进行了评价。结果：curr - nps在两种模型中都减少了病理性新生血管的形成，改善了OIR小鼠的血管完整性，减少了血管渗漏，保留了视网膜结构，减轻了细胞凋亡。与游离姜黄素相比，curc - nps的视网膜荧光分布更广，眼内荧光滞留时间更长。Cur-NPs抑制NLRP3ASCCaspase-1炎性小体和相关的VEGF/VEGFR2信号传导。遗传和药理学实验支持NLRP3信号在Cur-NPs抗血管生成作用中的功能贡献。多组学分析揭示了治疗相关的视网膜免疫细胞状态和代谢途径的变化。conbertcur - np联合治疗比单独治疗更能减少新生血管的形成。结论：cu - nps通过调节nlrp3相关的炎性血管生成信号抑制病理性RNV，同时改善视网膜保护和眼内潴留。这些发现支持进一步评估curr - nps作为vegf导向治疗的潜在上游抗炎辅助药物。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.