Killing three birds with one stone: Near-infrared light triggered nitric oxide release for enhanced photodynamic and anti-inflammatory therapy in refractory keratitis

Stubborn resistant bacteria, bacterial biofilms and severe inflammation are challenging issues in refractory keratitis treatment. Herein, we design a multifunctional near-infrared light-responsive nanoplatform for efficient therapy of refractory keratitis based on a "three-birds-with-one-stone" strategy, which integrates the bacteria targeting photodynamic therapy, nitric oxide (NO) sterilization, and NO-mediated anti-inflammatory property into one system. This nanoplatform (UCNANs) is constructed using the dual-emissive upconversion nanoparticles (UCNPs) as cores coated with mesoporous silica for the loading of photosensitizers with aggregation-induced emission (AIE) property and the grafting of NO donors and bacteria targeting molecules. Upon irradiation of 808 nm light, UCNPs simultaneously produce UV emission and visible emission to trigger NO release and reactive oxygen species (ROS) such as superoxide radical (O2•-) generation. Furthermore, O2•- resulting from PDT can react with NO to yield powerful oxidizing and nitrating agent peroxynitrite (ONOO-). The three components work synergistically to enhance the antibacterial outcome confirmed by in vitro and in vivo tests. The short-distance light excitation and excitation light absorption are important reasons for reducing the toxicity of materials, especially ultraviolet light damage. Moreover, bacteria elimination reduced endotoxin secretion and the released NO simultaneously inhibit the NF-κB pathways by regulating the expression of toll-like receptor 2 (TRL2) and tumor necrosis factor-α (TNF-α), which significantly relieves the inflammation of cornea. Given its excellent antibacterial and anti-inflammatory properties, UCNANs provides a competitive strategy for refractory keratitis therapy.