Cell-penetrating peptide-functionalized biomimetic nanovesicles for efficient cataract treatment via enhanced corneal penetration and lens-mitochondria dual targeting.

Cataract is the leading cause of blindness worldwide. While the oxidative stress homeostasis unbalance of the lens is a key pathological mechanism underlying cataract formation. Due to the lens being deeply embedded behind multiple biological barriers, there is no effective drug treatment for cataract currently. In this study, a multifunctional nanodelivery system (LSPE@Cur) was designed based on cell-penetrating peptide (PENE)-functionalized biomimetic membrane hybrid technology, which prevents cataract by collaboratively regulating mitochondrial homeostasis and oxidative stress balance. The system was constructed by curcumin (Cur)-lipid encapsulation technology combined with PENE functionalization, followed by exosome membrane fusion, creating a biomimetic nanocarrier with long ocular surface retention and deep penetration. This system enables homotypic targeting of lens epithelial cells via exosomal integrins and transmembrane transport proteins, while the PENE's multi-cationic structure ensures precise mitochondrial delivery, establishing a "tissue-organelle" dual-targeting approach. Cur activates the Nrf2 signaling pathway to upregulate the expression of cellular antioxidant enzymes, thereby establishing a long-lasting oxidative defense mechanism. In vitro and in vivo results demonstrated that LSPE@Cur eye drops efficiently maintain lens oxidative stress homeostasis and improve mitochondrial membrane potential. In summary, this study presents an innovative nanomedicine strategy for cataract treatment, offering both efficient delivery and sustained regulation.