Drug in Drug: Quorum Sensing Inhibitor in Star-Shaped Antibacterial Polypeptides for Inhibiting and Eradicating Corneal Bacterial Biofilms

Biofilm-related bacterial keratitis is a severe ocular infection that can result in drastic vision impairment and even blindness. However, the therapeutic efficiency of clinical antibiotic eyedrops is often compromised because the bacteria in the biofilms resist bactericide via the community genetic regulation, namely, bacterial quorum sensing. Herein, quercetin (QCT)-loaded star-shaped antibacterial peptide polymer (SAPP), QCT@SAPP, is developed based on a "drug" in a "drug" strategy for inhibiting and eradicating Pseudomonas aeruginosa biofilms on the cornea. The natural antibacterial peptide-mimic SAPP with the positively charged amphipathic structure not only enables QCT@SAPP to penetrate the biofilms readily but also selectively adheres to the highly negatively charged P. aeruginosa, releasing the loaded QCT into the bacteria to regulate quorum sensing by inhibiting lasI, lasR, rhlR, and rhlI. Thanks to its robust bactericidal ability from SAPP, QCT@SAPP can eliminate more than 99.99% of biofilms. Additionally, QCT@SAPP displayed outstanding performance in relieving ocular inflammation by significantly downregulating pro-inflammatory cytokines and profiting from scavenging reactive oxygen species by releasing QCT, which finally helps to restore visual function. In conclusion, QCT@SAPP, with good compatibility, exerts excellent therapeutic effects in a bacterial keratitis mice model, making it a promising candidate for controlling bacterial biofilm-induced infections, including bacterial keratitis.