Dry eye disease (DED) impacts ≈30% of the world's population and causes serious ocular discomfort and even visual impairment. Inflammation is one core cause of the DED vicious cycle, a multifactorial deterioration in DED process. However, there are also reactive oxygen species (ROS) regulating inflammation and other points in the cycle from the upstream, leading to treatment failure of current therapies merely targeting inflammation. Accordingly, the authors develop micelle‐based eye drops (more specifically p38 mitogen‐activated protein kinases (MAPK) inhibitor Losmapimod (Los)‐loaded and ROS scavenger Tempo (Tem)‐conjugated cationic polypeptide micelles, designated as MTem/Los) for safe and efficient DED management. Cationic MTem/Los improve ocular retention of conjugated water‐soluble Tem and loaded water‐insoluble Los via electrostatic interaction with negatively charged mucin on the cornea, enabling an increase in therapeutic efficiency and a decrease in dosing frequency. Mechanistically, MTem/Los effectively decrease ROS over‐production, reduce the expression of proinflammatory cytokines and chemokines, restrain macrophage proinflammatory phenotypic transformation, and inhibit cell apoptosis. Therapeutically, the dual‐functional MTem/Los suppress the inflammatory response, reverse corneal epithelial defect, save goblet cell dysfunction, and recover tear secretion, thus breaking the vicious cycle and alleviating the DED. Moreover, MTem/Los exhibit excellent biocompatibility and tolerability for potential application as a simple and rapid treatment of oxidative stress‐ and inflammation‐induced disorders, including DED.
Transition metal ions are served as disinfectant thousand years ago. However, the in vivo antibacterial application of metal ions is strongly restricted due to its high affinity with proteins and lack of appropriate bacterial targeting method. Herein, for the first time, Zn2+‐gallic acid nanoflowers (ZGNFs) are synthesized by a facile one‐pot method without additional stabilizing agents. ZGNFs are stable in aqueous solution while can be easily decomposed in acidic environments. Besides, ZGNFs can specifically adhere onto Gram‐positive bacteria, which is mediated by the interaction of quinone from ZGNFs and amino groups from teichoic acid of Gram‐positive bacteria. ZGNFs exhibit high bactericidal effect toward various Gram‐positive bacteria in multiple environments, which can be ascribed to the in situ Zn2+ release on bacterial surface. Transcriptome studies reveal that ZGNFs can disorder basic metabolic processes of Methicillin‐resistant Staphylococcus aureus (MRSA). Moreover, in a MRSA‐induced keratitis model, ZGNFs exhibit long‐term retention in the infected corneal site and prominent MRSA elimination efficacy due to the self‐targeting ability. This research not only reports an innovative method to prepare metal‐polyphenol nanoparticles, but also provides a novel nanoplatform for targeted delivery of Zn2+ in combating Gram‐positive bacterial infections.
Bacterial keratitis can lead to intraocular infection and even blindness without prompt and potent treatments. Currently, clinical abuse of antibiotics encouraged the evolution of resistant bacteria. Conventional antibiotic eye drops based keratitis treatment has been heavily restricted due to the lack of bactericidal efficiency and easy induction of bacterial resistance. Hence, developing an effective treatment strategy for bacterial keratitis is of great significance. In this work, we investigated ε‐poly‐ l ‐lysine (EPL)‐modified polydopamine (PDA) nanoparticles (EPL@PDA NPs)‐mediated antibacterial photothermal therapy (aPTT), to cope with methicillin‐resistant Staphylococcus aureus (MRSA)‐induced keratitis. The surface modification of cationic peptide EPL enables EPL@PDA NPs to specifically target negatively charged MRSA and induces local hyperthermia to kill the bacteria under low ambient temperature. Under near‐infrared (NIR) irradiation, the sterilization efficiency of EPL@PDA NPs suspension for MRSA in vitro was up to 99.96%. The EPL@PDA‐mediated aPTT presented potent antibacterial efficacy in treating MRSA‐induced keratitis with little corneal epithelial cytotoxicity and good biocompatibility. In conclusion, the bacterial‐targeting aPTT platform in this work provides a prospective method for the management of MRSA‐induced refractory bacterial keratitis.
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