BBB-Crossing Ionizable Upconversion Nanoparticles for Synergistic Therapy of Carbapenem-Resistant Central Nervous System Infection

Central nervous system (CNS) infections caused by carbapenem-resistant Enterobacteriaceae (CRE) biofilms pose a major critical healthcare challenge. These infections are difficult to treat due to the rising prevalence of antibiotic resistance and the restrictive nature of the blood-brain barrier (BBB), which limits therapeutic access to the brain tissue. To address this, we developed an innovative pH-responsive nanotherapeutic platform, UC@MOF@RB+MEM, integrating upconversion nanoparticles (UCNPs), a metal-organic framework (MOF), the photosensitizer rose bengal (RB), and the antibiotic meropenem (MEM). This design exhibited dual responsiveness to both pH and near-infrared (NIR) light, creating synergistic effects that disrupted biofilm and eradicated bacteria while mitigating neuroinflammation. During CNS inflammation, BBB permeability increased, enabling the ionizable UC@MOF@RB+MEM nanoparticles to cross the BBB and target infection sites. In the acidic microenvironment of the infection, these nanoparticles released MEM, RB, and Zn²⁺. Under 980-nm NIR light irradiation, RB generated reactive oxygen species (ROS), effectively disrupting the biofilms and bacterial membranes while inhibiting carbapenemase activity. The synergistic effect of photodynamic therapy (PDT) combined with MEM enabled rapid and effective eradication of CRE biofilm-associated bacteria. Simultaneously, the released Zn²⁺ mitigated nerve cell damage through anti-inflammatory and antioxidant effects. The dual actions markedly enhanced the efficacy of UC@MOF@RB+MEM in treating CNS infections in mouse models, offering promising prospects for managing CNS infections caused by CRE strains, and extending its potential to other hard-to-treat, antimicrobial-resistant infections.