Oral pH-responsive sodium alginate microspheres co-delivering Musca domestica cecropin and eugenol for anti-inflammatory therapy in sepsis.

Abstract

Systemic sepsis is a life-threatening syndrome driven by a dysregulated host response, leading to immune functional disorders, gut microbiota dysbiosis, and multi-organ failure. Previous studies have demonstrated that Musca domestica cecropin (MDC) and eugenol (EO) possess antibacterial, anti-inflammatory, and immunomodulatory activities, offering an approach to infection control. However, it is the vulnerability of therapeutic agents to the harsh gastrointestinal environment that severely limits the efficacy of oral delivery. To address these challenges, we developed a pH-responsive hydrogel microsphere system (MDC/EO/PDA-SA) for oral administration to treat systemic sepsis. This system comprises polydopamine (PDA) nanoparticles co-loaded with MDC and EO, encapsulated within a sodium alginate (SA) hydrogel matrix, leveraging the reliable pH-responsive behavior of SA for site-specific delivery. In vitro studies confirmed its controlled release profile: in Simulated Gastric Fluid (SGF), 24-hour release rates were minimal (19.96% for MDC and 14.42% for EO), whereas in Simulated Intestinal Fluid (SIF), they reached 72.95% for MDC and 64.03% for EO, demonstrating robust protection against gastric degradation and pH-responsive behavior. In a cecal ligation and puncture (CLP)-induced systemic sepsis model, MDC/EO/PDA-SA treatment significantly increased the survival rate to 66.6%. The system markedly reduced intestinal TNF-α and IL-6 levels (by 65.9% and 52.1%, respectively) and normalized myeloperoxidase (MPO) activity. Collectively, the treatment effectively alleviated systemic inflammation, mitigated oxidative stress, modulated immune responses, and restored intestinal homeostasis. These findings demonstrate that MDC/EO/PDA-SA provides effective intestinal-targeted delivery and multi-level therapeutic regulation, representing a promising oral strategy for the management of systemic sepsis.