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Immunomodulation of MiRNA-223-based nanoplatform for targeted therapy in retinopathy of prematurity
Keke Huang1, Zhiqing Lin1, Yuanyuan Ge1
1Institute of Advanced Materials for Nano-Bio Applications, School of Ophthalmology & Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Xi Road, Wenzhou, Zhejiang 325027, PR China.
Abstract:
Retinopathy of prematurity (ROP) is characterized by pathological angiogenesis and associated inflammation in the retina and is the leading cause of childhood blindness. MiRNA-223 (miR-223) drives microglial polarization toward the anti-inflammatory phenotype and offers a therapeutic approach to suppress inflammation and consequently pathological neovascularization. However, miRNA-based therapy is hindered by the low stability and non-specific cell-targeting ability of delivery systems. In the present study, we developed folic acid-chitosan (FA-CS)-modified mesoporous silica nanoparticles (PMSN) loaded with miR-223 to regulate retinal microglial polarization. The FA-CS/PMSN/miR-223 nanoparticles exhibited high stability and loading efficiency, achieved targeted delivery, and successfully escaped from lysosomes. In cultured microglial cells, treatment with FA-CS/PMSN/miR-223 nanoparticles upregulated the anti-inflammatory gene YM1/2 and IL-4RA, and downregulated the proinflammatory genes iNOS, IL-1β, and IL-6. Notably, in a mouse oxygen-induced retinopathy model of ROP, intravitreally injected FA-CS/PMSN/miR-223 nanoparticles (1 μg) decreased the retinal neovascular area by 52.6%. This protective effect was associated with the reduced and increased levels of pro-inflammatory (M1) and anti-inflammatory (M2) cytokines, respectively. Collectively, these findings demonstrate that FA-CS/PMSN/miR-223 nanoparticles provide an effective therapeutic strategy for the treatment of ROP by modulating the miR-223-mediated microglial polarization to the M2 phenotype.
Insights
Novel nanoparticles deliver microRNA-223 (miR-223) to treat retinopathy of prematurity (ROP). This targeted therapy reduces retinal inflammation and neovascularization, offering a promising approach for childhood blindness prevention.
Area of Science:
- Ophthalmology
- Nanomedicine
- Molecular Biology
Background:
- Retinopathy of prematurity (ROP) causes childhood blindness due to retinal pathological angiogenesis and inflammation.
- MicroRNA-223 (miR-223) shows potential for suppressing ROP-related inflammation and neovascularization.
- Current miRNA delivery methods face challenges with stability and targeted cell delivery.
Purpose of the Study:
- To develop a stable, targeted nanoparticle delivery system for miR-223 to treat ROP.
- To investigate the efficacy of folic acid-chitosan (FA-CS)-modified mesoporous silica nanoparticles (PMSN) loaded with miR-223 in regulating microglial polarization.
- To evaluate the therapeutic potential of this system in an animal model of ROP.
Main Methods:
- FA-CS/PMSN/miR-223 nanoparticles were synthesized and characterized for stability and loading efficiency.
- The nanoparticles' ability to target microglial cells and escape lysosomes was assessed.
- In vitro studies evaluated the modulation of inflammatory gene expression in microglial cells.
- An oxygen-induced retinopathy mouse model was used to assess the in vivo therapeutic effect of intravitreal injection.
Main Results:
- FA-CS/PMSN/miR-223 nanoparticles demonstrated high stability, efficient loading, targeted delivery, and lysosomal escape.
- In vitro, nanoparticles upregulated anti-inflammatory markers (YM1/2, IL-4RA) and downregulated pro-inflammatory markers (iNOS, IL-1β, IL-6).
- In vivo, intravitreal injection of nanoparticles reduced the retinal neovascular area by 52.6% in the ROP mouse model.
- Treatment modulated cytokine profiles, shifting towards an anti-inflammatory M2 microglial phenotype.
Conclusions:
- FA-CS/PMSN/miR-223 nanoparticles represent an effective strategy for ROP treatment.
- The nanoparticles successfully deliver miR-223, modulating microglial polarization to an anti-inflammatory M2 phenotype.
- This approach offers a promising therapeutic avenue for retinopathy of prematurity by reducing pathological neovascularization.
