Abstract

Biofilm-associated infections remain a major challenge, as the inherent recalcitrance of the extracellular polymeric substance matrix renders conventional antibiotics ineffective, further driving antimicrobial resistance. To address this, combination therapies have emerged as a potent strategy to enhance therapeutic outcomes. In this study, a dual-functional, antibiotic-free nanoplatform was designed to eradicate biofilms through combined quorum sensing (QS) inhibition and chemodynamic therapy (CDT). This nanoplatform consists of calcium peroxide (CaO2) nanoparticles coated with a quercetin/copper ion (Qe/Cu2+) complex. Upon exposure to the acidic biofilm microenvironment, the Qe/Cu2+ complex dissociates, releasing Qe and Cu2+ while exposing the CaO2 core. The subsequent reaction of CaO2 with water generates hydrogen peroxide, which is then catalyzed by Cu2+ via a Fenton-like reaction to produce highly bactericidal hydroxyl radicals. Simultaneously, Qe disrupts bacterial QS pathways, attenuating pathogenicity and sensitizing the biofilm-embedded bacteria to oxidative damage. This antibiotic-free nanoplatform demonstrated robust in vitro antibiofilm activity against Pseudomonas aeruginosa and Staphylococcus aureus, while significantly reducing bacterial colonization and accelerating wound healing in an infected mouse model, suggesting that the synergetic integration of QS inhibition and CDT represents a promising strategy for combating biofilm-associated infections.