A novel biomimetic and redox-responsive hybrid lipid polymer nanoparticle for targeting sepsis microenvironment and modulating inflammation.

Bacterial sepsis is a life-threatening syndrome caused by a dysregulated immune response to infection. Despite advances in therapeutic strategies, it remains a leading cause of mortality worldwide. This study developed a redox-responsive, biomimetic hybrid lipid-polymer nanocarrier (SC-HLPN) incorporating a novel stearic acid-cystamine-chlorogenic acid (S-ss-CG) conjugate with polyethylenimine (PEI) to target the ADAM10 receptor and its associated inflammatory pathway (NLRP3 inflammasome activation). The design enables binding to ADAM10, scavenging its natural substrate, alpha-hemolysin (A-H), and the selective release of antibiotics within the sepsis microenvironment by reducing condition-triggered disulfide bond cleavage, resulting in the release of vancomycin (VCM). The S-ss-CG conjugate was synthesized and characterized by FTIR, 1H NMR spectroscopy, and LC/MS. Its interactions with ADAM10 and A-H were confirmed in silico, showing binding affinities of -53.55 kcal/mol and -36.29 kcal/mol, respectively, and validated in vitro via microscale thermophoresis (MST), with dissociation constants of 16.766 µM (ADAM10) and 1.8661 µM (A-H). The optimized SC-HLPN demonstrated favorable physicochemical properties, high biocompatibility, and stability. Under reducing conditions, particle size increased due to disulfide bond cleavage, enabling accelerated VCM release, achieving complete release within 48 hrs, compared to 72 hrs under physiological conditions. Moreover, SC-HLPN exhibited superior in vitro antibacterial activity, with lower minimum inhibitory concentrations and faster killing kinetics than bare VCM. It also showed potent antioxidant capacity, protected cells from intracellular ROS, and exerted strong anti-inflammatory effects in LPS-induced cells. In a murine MRSA sepsis model, SC-HLPN achieved 88.3% bacterial clearance, significantly reduced IL-1β, IL-18, and IL-6 levels by 3.7, 2.8, and 1.8-fold, respectively, and mitigated organ injury. These results highlight the promise of S-ss-CG as a multifunctional platform for targeted and efficient antibiotic delivery in the treatment of sepsis.