Liposomal delivery of antibiotic loaded nucleic acid nanogels with enhanced drug loading and synergistic anti-inflammatory activity against S. aureus intracellular infections

Abstract

The persistence of <i>Staphylococcus aureus</i> has been accredited to its ability to escape immune response via host cell invasion. Despite the efficacy of many antibiotics against <i>S. aureus</i>, the high extracellular concentrations of conventional antibiotics required for bactericidal activity is limited by their low cellular accumulation and poor intracellular retention. While nanocarriers have received tremendous attention for antibiotic delivery against persistent pathogens, they suffer daunting challenges such as low drug loading, poor retention and untimely release of hydrophilic cargos. Here, a hybrid system (Van_DNL) is fabricated wherein nucleic acid nanogels are caged within a liposomal vesicle for antibiotic delivery. The central principle of this approach relies on exploiting non-covalent electrostatic interactions between cationic cargos and polyanionic DNA to immobilize antibiotics and enable precise temporal release against intracellular <i>S. aureus. In vitro</i> characterization of Van_DNL revealed a stable homogenous formulation with circular morphology and enhanced vancomycin loading efficiency. The hybrid system significantly sustained the release of vancomycin over 24 h compared to liposomal or nanogel controls. Under enzymatic conditions relevant to <i>S. aureus</i> infections, lipase triggered release of vancomycin was observed from the hybrid. While using Van_DNL to treat <i>S. aureus</i> infected macrophages, a dose dependent reduction in intracellular bacterial load was observed over 24 h and exposure to Van_DNL for 48 h caused negligible cellular toxicity. Pre-treatment of macrophages with the antimicrobial hybrid resulted in a strong anti-inflammatory activity in synergy with vancomycin following endotoxin stimulation. Conceptually, these findings highlight these hybrids as a unique and universal platform for synergistic antimicrobial and anti-inflammatory therapy against persistent infections.