A biomimetic nanoparticle for the treatment of sepsis via anti-inflammatory, antioxidant, and anticoagulant mechanisms.

Abstract

Sepsis is a life-threatening syndrome resulting from a dysregulated immune response to infection, characterized by high morbidity and mortality. Excessive oxidative stress, inflammatory cytokine storms, and hyperactivated coagulation cascades collectively drive multiple organ dysfunction, posing major challenges in clinical treatment. Quercetin (Que), a natural flavonoid with anti-inflammatory, antioxidant, and anticoagulant activities, has shown considerable potential as a therapeutic agent for sepsis. Nevertheless, its clinical translation is limited by poor aqueous solubility, chemical instability, and low bioavailability. To overcome these limitations, we designed a biomimetic nanoplatform based on mesoporous polydopamine (mPDA) nanoparticles for the efficient delivery of Que. Furthermore, to enhance the biocompatibility, circulation time, and inflammation-targeting capability, the Que-loaded mPDA nanoparticles were coated with platelet membranes (PM), yielding mPDA-Que@PM nanoparticles. In vitro, mPDA-Que@PM exhibited efficient ROS scavenging, significantly suppressed LPS-induced secretion of TNF-α, IL-6, and IL-1β, and inhibited the TLR4/NF-κB signaling pathway. In a CLP-induced sepsis mouse model, treatment with mPDA-Que@PM alleviated hepatic and pulmonary inflammation and oxidative damage, reduced serum thrombin and thrombin-antithrombin complex levels, improved coagulation abnormalities, and significantly increased survival. Additionally, the mPDA-Que@PM demonstrated excellent hemocompatibility and biosafety. This study presents a multifunctional, platelet-mimicking nanomedicine capable of simultaneously modulating oxidative stress, inflammation, and coagulation imbalance, offering a promising strategy for precise and synergistic intervention in sepsis.