Synergistic dual sensitizer integrated ZIF-8 nanoplatform for enhanced sonodynamic eradication of deep-seated drug-resistant biofilms.

Deep-seated biofilm infections caused by drug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), remain a major clinical challenge due to restricted antibiotic penetration, hypoxic microenvironments, and intrinsic tolerance provided by biofilm structures. Sonodynamic therapy (SDT), which utilizes ultrasound (US) to activate sensitizers for reactive oxygen species (ROS) generation, has emerged as a promising modality with advantages such as tissue penetration and biofilm disruption. Nevertheless, sonosensitizers, particularly organic small molecules, are constrained by poor physicochemical stability and inadequate specificity toward infection sites. Here, we present a dual sensitizer integrated sonodynamic agent (DiSONA), engineered by co-encapsulating sonosensitizers Rose bengal and curcumin within a zeolitic imidazolate framework, ZIF-8. The DiSONA exhibits high drug-loading capacity, a positively charged surface that enhances bacterial targeting, and a pH/US-responsive release profile tailored to the acidic infection microenvironments. Upon US exposure, the DiSONA generated substantially higher overall ROS levels than the corresponding single-sensitizer formulations, resulting in potent antibacterial activity against planktonic MRSA and mature MRSA biofilms (>99.999% and >99.9% killing rates, respectively). In a murine subcutaneous abscess model, DiSONA-mediated SDT yielded >99.99% MRSA clearance without observable systemic toxicity. This work establishes a paradigm for combating deep-seated drug-resistant biofilm infections by integrating dual sonodynamic mechanisms with nanocarrier engineering.