Dual Corona Vesicles with Intrinsic Antibacterial and Enhanced Antibiotic Delivery Capabilities for Effective Treatment of Biofilm-Induced Periodontitis

Abstract

Periodontitis is a common disease caused by plaque biofilms, which are important pathogenic factors of many diseases and may be eradicated by antibiotic therapy. However, low-dose antibiotic therapy is a complicated challenge for eradicating biofilms as hundreds (even thousands) of times higher concentrations of antibiotics are needed than killing planktonic bacteria. Polymer vesicles may solve these problems <i>via</i> effective antibiotic delivery into biofilms, but traditional single corona vesicles lack the multifunctionalities essential for biofilm eradication. In this paper, we aim to effectively treat biofilm-induced periodontitis using much lower concentrations of antibiotics than traditional antibiotic therapy by designing a multifunctional dual corona vesicle with intrinsic antibacterial and enhanced antibiotic delivery capabilities. This vesicle is co-assembled from two block copolymers, poly(ε-caprolactone)-<i>block</i>-poly(lysine-<i>stat</i>-phenylalanine) [PCL-<i>b</i>-P(Lys-<i>stat</i>-Phe)] and poly(ethylene oxide)-<i>block</i>-poly(ε-caprolactone) [PEO-<i>b</i>-PCL]. Both PEO and P(Lys-<i>stat</i>-Phe) coronas have their specific functions: PEO endows vesicles with protein repelling ability to penetrate extracellular polymeric substances in biofilms ("stealthy" coronas), whereas P(Lys-<i>stat</i>-Phe) provides vesicles with positive charges and broad spectrum intrinsic antibacterial activity. As a result, the dosage of antibiotics can be reduced by 50% when encapsulated in the dual corona vesicles to eradicate <i>Escherichia coli</i> or <i>Staphylococcus aureus</i> biofilms. Furthermore, effective <i>in vivo</i> treatment has been achieved from a rat periodontitis model, as confirmed by significantly reduced dental plaque, and alleviated inflammation. Overall, this "stealthy" and antibacterial dual corona vesicle demonstrates a fresh insight for improving the antibiofilm efficiency of antibiotics and combating the serious threat of biofilm-associated diseases.