Dual-Targeting Sepsis-Associated Inflammation and Infection Using Linoleic Acid-Based Lipid-Polymer Hybrid Nanoparticles

Abstract

Bacterial sepsis is a critical and life-threatening condition resulting from a dysregulated host immune response to infection and remains one of the foremost causes of mortality worldwide. In this study, a biomimetic hybrid lipid-polymer nanocarrier (VCM-LIN-P2O NPs) was designed to target the ADAM10 and TLR2 receptor pathways through integrating linoleic acid (LIN) and poly(2-ethyl-2-oxazoline) (P2O). This engineered nanoplatform attenuates excessive inflammation via concurrent binding to ADAM10 and TLR2 while ensuring targeted delivery of vancomycin (VCM) to infection sites. The potential of LIN to competitively bind to ADAM10 and TLR2 was initially examined through molecular docking and subsequently validated using microscale thermophoresis (MST), confirming the potential ability of LIN to downregulate the inflammation associated with ADAM10 and TLR2 activation. The optimized VCM-LIN-P2O NPs displayed desirable physicochemical characteristics, excellent biocompatibility, and high stability, along with a sustained drug release profile extending up to 48 hrs. Furthermore, the nanocarrier exhibited enhanced in vitro antibacterial performance compared to bare VCM, along with significant antioxidant and anti-inflammatory activity, in LPS-stimulated macrophages. In a murine MRSA-induced sepsis model, treatment with VCM-LIN-P2O NPs resulted in marked bacterial clearance from major organs and the bloodstream, accompanied by a significant reduction in TNF-α, IL-1β, and IL-18 levels, thereby alleviating organ damage. Therefore, these findings establish VCM-LIN-P2O NPs as a promising multifunctional nanoplatform for targeted antibiotic delivery and effective sepsis therapy.