Non-invasive and efficient diabetic retinal mitochondrial repair nanoplatform based on engineered endothelial mitochondrial-derived vesicles with dynamic integrated stress response modulation

Abstract

Diabetic retinopathy (DR) is driven by chronic oxidative stress and mitochondrial dysfunction, yet effective, non-invasive strategies for mitochondrial quality control (MQC) that can traverse the blood–retinal barrier (BRB) remain limited. Here, we systematically develop and investigate a bioengineered nanoplatform—endothelial mitochondria-derived vesicles (EMDVs) from retinal microvascular cells. Through optimized functional extraction and membrane potential-preserving bioengineering, EMDVs retain critical mitochondrial membrane potential and adenosine triphosphate synthesis capabilities. Upon Coenzyme Q10 (CoQ10) modification, EMDVs exhibit potent antioxidant activity. Kinetic and phenotypic recovery assays demonstrate that EMDVs non-invasively penetrate the retina and efficiently deliver CoQ10 across the BRB to all retinal layers, restoring mitochondrial homeostasis and remodeling antioxidant defenses. Transcriptomic and mechanistic analyses further reveal that topical administration of EMDVs and CoQ10-engineered vesicles dynamically modulates the disease-dependent eIF2α-ATF4-CHOP-integrated stress response axis, facilitating repair and remodeling of the retinal barrier, particularly the microvasculature, in both early- and late-stage DR. Long-term in vivo safety evaluation confirms no systemic toxicity or local inflammation. This study introduces a mitochondria-derived vesicle nanoplatform with high BRB permeability and efficient MQC function, highlighting its translational potential as a dynamic, targeted therapeutic strategy for mitochondrial dysfunction-related degenerative diseases and versatile drug delivery across biological barriers.