Endothelial mitochondrial-derived vesicles (EMDVs) with retinal targeted homing properties dynamically modulate the eIF2α-ATF4-CHOP signaling pathway and efficiently restore mitochondrial homeostasis in diabetic retina.

Diabetic retinopathy (DR) is characterized by persistent oxidative stress and compromised mitochondrial integrity, posing significant challenges for effective, non-invasive mitochondrial therapy. Here, we present a bioengineered nanoplatform composed of endothelial mitochondria-derived vesicles (EMDVs) sourced from retinal microvascular endothelial cells (RMECs), designed for precise retinal targeting. EMDVs retain critical mitochondrial membrane components, bioenergetic function, and intrinsic antioxidant capacity, which can be further amplified by Coenzyme Q10 (CoQ10) loading. In contrast, endothelial cell-derived exosomes (EEXOs) and CoQ10-loaded EEXOs (EEXOs-CoQ10) lack mitochondrial membranes, functional bioenergetics, retinal homing ability, and mitochondrial homeostasis-regulating capacity. Upon topical administration, EMDVs traverse the blood-retinal barrier efficiently, selectively accumulate in retinal microvasculature, restore mitochondrial dynamics, and enhance cellular antioxidant defenses. Mechanistic analyses reveal that EMDVs dynamically modulate the eIF2α–ATF4–CHOP stress response pathway, promoting repair of the retinal barrier and vascular microenvironment in both early and advanced DR. Long-term studies confirm the nanoplatform is well-tolerated, with no systemic or local adverse effects. These findings establish EMDVs as a targeted, non-invasive strategy for mitochondrial quality control and retinal repair, offering a versatile approach for treating mitochondrial dysfunction-related ocular diseases. GRAPHICAL ABSTRACT: [Figure: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-025-03929-3.