Polymer-based gene-drug co-delivery system effectively inhibits pathologic retinal neovascularization through dual anti-inflammatory and anti-neovascular actions

Retinal neovascularization is one of the most prevalent fundus neovascular diseases, affecting vision and potentially leading to severe complications, such as retinal detachment or irreversible blindness. Current treatments primarily involve intravitreal injections (IVT) of anti-vascular endothelial growth factor (anti-VEGF) agents. However, such treatment often requires repeated injections, develop incomplete responses, and are associated with adverse effects. Therefore, novel therapeutic agents need to be developed that exhibit low side effects and improved therapeutic efficacy of retinal neovascularization. Herein, we develop a novel polymeric gene carrier, phenylboronic acid-modified linear polyethylenimine (LPEI-PBA) that is capable of loading plasmid expressing short hairpin RNA ( p shVEGF), which self-assembles with dexamethasone sodium phosphate (DSP) via electrostatic interactions to form a polymer-based gene-drug co-delivery system ( D SP/L P EI- P BA/ p sh V EGF, DPPV ) for combined neovascularization inhibition. DSP not only exerts anti-inflammatory effects but also enhances the transfection efficiency of LPEI-PBA. DPPV demonstrated favorable anti-neovascular effects both in vitro and in vivo . In an oxygen-induced retinopathy model, a single intravitreal administration of DPPV can significantly inhibited pathological neovascularization, accompanied by the downregulation of glial activation markers glial fibrillary acidic protein (GFAP) and ionized calcium-binding junction molecule 1 (IBA-1), as well as the pro-inflammatory factor interleukin-1β (IL-1β), and the upregulation of the anti-inflammatory factor ARG-1. In conclusion, DPPV nanoparticles effectively inhibit pathological retinal neovascularization through dual anti-inflammation and anti-angiogenesis, showing a promising therapeutic option for fundus neovascularization diseases.