Hybrid cell-membrane-coated biomimetic nanoparticles for targeted noninvasive intervention in early diabetic retinopathy.

Diabetic retinopathy (DR), a diabetes mellitus-induced ocular complication, demands non-invasive and effective early interventions to halt disease progression. Here, we developed biomimetic hybrid nanoparticles ([RBC-EC]-NPs) by coating fused membranes derived from red blood cells (RBC) and retinal endothelial cells (EC) on poly (lactic-co-glycolic acid) (PLGA) cores. Optimizing the membrane-to-PLGA ratio to 1:2 yielded stable nanoparticles that preserved critical membrane proteins, including CD47 (for immune evasion) and vascular endothelial cadherin (for endothelial targeting). The dual-coating strategy synergistically enhanced retinal endothelial targeting, suppressed pathological EC migration, and prolonged systemic circulation. In a STZ-induced diabetic rat model, intravenously administered [RBC-EC]-NPs selectively accumulated in retinal vasculature, significantly downregulating vascular endothelial growth factor expression, mitigating vascular leakage, thereby reducing formation of acellular capillary. Transcriptomic analysis revealed nanoparticle-mediated restoration of lysosomal function, lipid metabolism, and tumor necrosis factor-associated inflammatory pathways. Notably, systemic treatment also ameliorated dyslipidemia without inducing hematological or hepatic toxicity. Comprehensive biosafety evaluations confirmed the absence of acute tissue damage. Together, these findings demonstrated that [RBC-EC]-NPs could represent a potent and targeted nanotherapeutic platform for early-stage DR intervention, combining dual-cell membrane advantages with high biocompatibility. STATEMENT OF SIGNIFICANCE: Diabetic retinopathy (DR) remains a leading cause of blindness, and current treatments are largely invasive and limited to late stages. Here, we developed hybrid red blood cell-endothelial cell membrane-coated nanoparticles ([RBC-EC]-NPs) as a minimally invasive intravenous therapy. These biomimetic NPs uniquely combine endothelial targeting and immune evasion, enabling selective retinal vascular accumulation. Mechanistically, [RBC-EC]-NPs reduced VEGF overexpression, restored lysosomal-autophagy function, suppressed inflammation, and rebalanced lipid metabolism, thereby alleviating vascular leakage, preserving retinal microcirculation, and improving systemic lipid profiles in diabetic rat models. This study demonstrates the potential of [RBC-EC]-NPs as a safe, multifunctional therapeutic platform that targets the metabolic and vascular pathogenesis of early DR, offering a promising alternative to current intravitreal interventions.