A multistage microRNA nanotherapeutic to address fibrosis of bacterial keratitis

Abstract

Bacterial keratitis (BK) is a leading cause of visual impairment and blindness. The conventional treatment involves frequent instillation of antibiotics at the lesion site. However, this approach not only leads to bacterial resistance but also suffers from poor bioavailability and often overlooks the damage caused by secondary scarring following corneal infections. In this study, we have developed a multistage nanotherapeutic (DHA-lys@miRNA) to address both anti-infection and secondary scarring hyperplasia during the treatment of bacterial keratitis. Specifically, docosahexaenoic acid (DHA) and ε-polylysine (ε-PL) were successfully self-assembled to form an amphipathic cationic nanocarrier, DHA-lys, which can complex with microRNA to form nanotherapeutics. This nanosystem exhibits potent bacteriostatic effects and amphiphilicity, enabling it to bind to the tear film lipid layer and conjunctival mucosal layer, thereby significantly enhancing its residence time and penetration in the corneal tissue. This, in turn, improves the bioavailability of the drug in bacterial keratitis. Furthermore, we have identified miR-361–3p as a key microRNA through database screening and a series of experiments. This microRNA can specifically inhibit corneal fibrosis by interrupting the crosstalk between corneal stromal cells and myofibroblasts in a BK mouse model in vivo. Overall, this study offers innovative insights into the treatment of infectious eye diseases, leveraging the potential of nucleic acid nanotherapeutics.