Thermosensitive hydrogel composite with si-Cx43 nanoparticles and anti-VEGF agent for synergistic treatment of diabetic retinopathy

Diabetic retinopathy (DR) is characterized by pathological angiogenesis, inflammation, and retinal neurodegeneration, leading to vision loss. Current therapies, such as anti-VEGF agents, face challenges of low bioavailability and frequent invasive injections. Connexin43 (Cx43), a gap junction protein, plays a key role in DR progression through its modulation of inflammation and vascular dysfunction. A thermosensitive hydrogel composite was developed to encapsulate siRNA targeting Cx43 (si-Cx43) nanoparticles (NPs) and anti-VEGF (Avastin). The hydrogel was characterized for gelation, injectability, and degradation. In vitro studies evaluated the cytotoxicity, anti-angiogenic effects, and permeability regulation in hyperglycemic retinal cells under hyperglycemic conditions. In vivo therapeutic efficacy was assessed in a diabetic retinopathy rat model. si-Cx43-NPs demonstrated high siRNA encapsulation efficiency and stability, effectively silencing Cx43 expression in retinal endothelial cells. The hydrogel exhibited excellent injectability, temperature-sensitive gelation, and controlled degradation. In vitro, si-Cx43-NPs@Avastin-hydrogel significantly suppressed VEGF expression, reduced angiogenesis, and restored cell permeability under hyperglycemic conditions. In vivo , the hydrogel composite reduced neovascularization, inflammation, and apoptosis, restoring retinal structure and function more effectively than either single-agent treatment alone. Biocompatibility studies confirmed minimal toxicity and favorable degradation. The si-Cx43-NPs@Avastin-hydrogel provides a synergistic and minimally invasive therapeutic strategy for DR by targeting angiogenesis, inflammation, and neuroprotection with sustained drug delivery.