Exosome-like nanovesicles derived from Lycium barbarum L. target angiogenesis and epithelial barrier impairment to attenuate diabetic retinopathy and synergize with anti-VEGF therapy

First study of LB-Exos in modulating ocular disease. • LB-Exos present as natural, multi-target nanotherapeutics for diabetic retinopathy. • LB-Exos protect against oxidative stress, restore blood-retinal barrier integrity. • LB-Exos downregulate the HIF-1α/VEGF/VEGFR2 axis. • LB-Exos exhibit synergistic effect with standard anti-VEGF therapy. The growing interest in plant-derived extracellular vesicles (EVs) as nanotherapeutics has positioned Lycium barbarum L. EVs (LB-Exos) as a promising candidate for treating diabetic retinopathy (DR), a condition characterized by pathological angiogenesis and blood-retinal barrier (BRB) dysfunction. This study investigates the multifaceted therapeutic effects of LB-Exos, isolated from fresh goji berries and characterized for their bioactive metabolite cargo. In vitro, LB-Exos protected ARPE-19 cells from apoptosis by modulating the MAPK pathway and the Bcl-2/BAX/caspase-3 axis. In HUVECs, LB-Exos suppressed angiogenesis by downregulating the HIF-1α/VEGF/VEGFR2 axis and ANGPT2, showing synergistic effects with the standard therapy of bevacizumab (BVZ). These mechanisms were validated in a streptozotocin-induced diabetic mouse model, where LB-Exos treatment alleviated retinal pathology, reduced neovascularization, and restored BRB integrity by upregulating tight junction proteins. Our study establishes LB-Exos as a novel, natural nanoplatform that concurrently targets multiple pathological pathways in DR. This work elucidates the multifaceted therapeutic potential of PDEVs in ophthalmology and highlights their complementary mechanism to enhance current anti-VEGF therapy. Download: Download high-res image (321KB) Download: Download full-size image