Enzyme-responsive biomimetic solid lipid nanoparticles for antibiotic delivery against hyaluronidase-secreting bacteria

In this work, a potent hyaluronidase inhibitor (ascorbyl stearate (AS)) was successfully employed to design vancomycin-loaded solid lipid nanoparticles (VCM-AS-SLNs) with biomimetic and enzyme-responsive features, to enhance the antibacterial efficacy of vancomycin against bacterial-induced sepsis. The VCM-AS-SLNs prepared were biocompatible and had appropriate physicochemical parameters. The VCM-AS-SLNs showed an excellent binding affinity to the bacterial lipase. The in vitro drug release study showed that the release of the loaded vancomycin was significantly accelerated by the bacterial lipase. The in silico simulations and MST studies confirmed the strong binding affinity of AS and VCM-AS-SLNs to bacterial hyaluronidase compared to its natural substrate. This binding superiority indicates that AS and VCM-AS-SLNs could competitively inhibit the effect of hyaluronidase enzyme, and thus block its virulence action. This hypothesis was further confirmed using the hyaluronidase inhibition assay. The in vitro antibacterial studies against sensitive and resistant Staphylococcus aureus revealed that the VCM-AS-SLNs had a 2-fold lower minimum inhibitory concentration, and a 5-fold MRSA biofilm elimination compared to the free vancomycin. Furthermore, the bactericidal-kinetic showed a 100% bacterial clearance rate within 12 h of treatment with VCM-AS-SLNs, and <50 % eradication after 24 h for the bare VCM. Therefore, the VCM-AS-SLN shows potential as an innovative multi-functional nanosystem for effective and targeted delivery of antibiotics.