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

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.