Novel lipid and ascorbyl stearate biomimetic vancomycin-loaded nanostructured lipid carrier therapy for bacterial infections and sepsis.

The global burden of methicillin-resistant Staphylococcus aureus (MRSA)-associated sepsis necessitates innovative therapeutic strategies. In this study, we developed a multifunctional biomimetic nanostructured lipid carrier (NLC) using a synthesized lipid and ascorbyl stearate to simultaneously deliver vancomycin (VCM) and target the reactive oxygen species (ROS) and the A Disintegrin and Metalloproteinase 10 (ADAM10)-alpha-hemolysin (AHL) pathways implicated in sepsis pathogenesis. The NLC-VCM was formulated via a nanoprecipitation-ultrasonication method and underwent comprehensive physicochemical characterization. Its biological performance was evaluated through in vitro antibacterial, antioxidant, and anti-inflammatory assays, followed by validation in a mice sepsis model. The optimized NLC-VCM exhibited a monodisperse spherical morphology, sustained biphasic drug release over 48 hours, and high biocompatibility. The formulation demonstrated superior antibacterial efficacy, evidenced by a two-fold lower MIC and complete MRSA clearance within 12 hours compared to bare VCM. Flow cytometry confirmed the potent bactericidal activity, with only 34.4% of MRSA cells remaining viable and the majority (61.4%) being non-viable. Furthermore, in vitro antioxidant and anti-inflammatory assays confirmed significant ROS scavenging capacity and suppression of LPS-induced IL-1β and TNF-α in RAW264.7 cells. In the mice sepsis model, NLC-VCM treatment significantly reduced bacterial load (73.9% CFU reduction) and IL-18 levels compared to bare VCM. These findings show the potential of NLC-VCM as a therapeutic platform that synergistically combines antibacterial action with host-directed immunomodulation to combat MRSA infections and sepsis.