A fast-slow liposome based "orthodox-unexpected interplay" strategy for bacterial otitis media and associated hearing loss.

Otitis media (OM), the most common infectious disease affecting the middle ear, is a major cause of hearing loss worldwide. It is primarily caused by bacteria such as Staphylococcus aureus (S. aureus), which invade the tympanum, form dense biofilms, and induce persistent inflammation. Conventional treatments rely on multiple doses of antibiotics, which often lead to drug resistance and ineffectiveness. Here, we introduce a fast-slow liposome platform (lip@Lys/NC) based on an "orthodox-unexpected interplay" principle, integrating bacteriolysis, quorum sensing inhibition, and anti-inflammation for effective biofilm disruption and inflammation reduction. Lip@Lys/NC consists of lysostaphin (Lys, for rapid bacteriolysis) and chitosan nanoparticles loaded with curcumin/tanshinone IIA (CUR/TSIIA, for sustained anti-biofilm and anti-inflammation effects), allowing immediate bacterial killing with prolonged therapeutic effect. In vitro studies demonstrate that lip@Lys/NC exhibits potent antibacterial activity against methicillin-resistant S. aureus (MRSA), disrupts biofilms, inhibits quorum sensing, and decreases pro-inflammatory factors. Notably, this synergistic effect does not induce drug resistance, unlike traditional antibiotics. In guinea pig models of S. aureus/MRSA-induced acute and chronic OM, lip@Lys/NC effectively reduces middle-ear inflammation and dismantles bacterial biofilms. Moreover, it protects cochlear hair cells, reduces inflammatory mediator infiltration into the inner ear, and prevents hearing loss, achieving an efficient "orthodox-unexpected interplay" strategy for OM treatments. This integrated system offers a promising non-antibiotic therapeutic approach for MRSA-associated OM, addressing both pathogen elimination and hearing preservation.