Phage-liposome nanoconjugates for orthopedic biofilm eradication

Abstract

Infection by multidrug-resistant (MDR) bacteria has become one of the biggest threats to public health worldwide. One reason for the difficulty in treatment is the lack of proper delivery strategies into MDR bacterial biofilms, where the thick extracellular polymeric substance (EPS) layer impedes the penetration of antibiotics and nanoparticles. Here, we propose a novel bioactive nanoconjugate of drug-loaded liposomes and bacteriophages for targeted eradication of the MDR biofilms in orthopedic infections. Phage Sb-1, which has the ability to degrade EPS, was conjugated with antibiotic-loaded liposomes. Upon encountering the biofilm, phage Sb-1 degrades the EPS structure, thereby increasing the sensitivity of bacteria to antibiotics and allowing the antibiotics to penetrate deeply into the biofilm. As a result, effective removal of MDR bacterial biofilm was achieved with low dose of antibiotics, which was proved in this study by both in vitro and in vivo investigations. Notably, in the rat prosthetic joint infection (PJI) model, we found that the liposome-phage nanoconjugates could effectively decrease the bacterial load in the infected area and significantly promote osteomyelitis recovery. It is therefore believed that the conjugation of bacteriophage and liposomes could open new possibilities for the treatment of orthopedic infections, possibly other infections in the deep tissues. The proposed liposome-phage nanoconjugates (Lip@Phage) can achieve robust biofilm cell elimination through phage-assisted antibiotic delivery therapy, and it effectively utilizes the remaining susceptible antibiotics by loading them into the liposomes, while the encoded depolymerases in the phage tail facilitate EPS degradation, promoting antibiotic penetration into the deep layers of the biofilm. • An EPS degrading nanoconjugate was designed to facilitate antibiotic delivery into the biofilm. • The nanoconjugate was developed by chemical conjugation of EPS degrading bacteriophage and antibiotic-loaded liposomes. • Benefiting from the depolymerase of phages, the biofilm can be removed at a low dose of antibiotics. • .The bacteriophage-liposome nanoconjugates show potent antibacterial activity in prosthetic joint infection models. • The components have been approved for clinical usage, therefore the nanoconjugates can be easily translated into clinics.

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