Picroside II-Encapsulated Nanoformulations as Pyroptosis Inhibitor Alleviate Cytokine Storms and Remodel Gut Microbiota Disturbances

Sepsis still remains the leading cause of morbidity and mortality in clinical settings, characterized by pyroptosis-induced cytokine release syndrome, multiple organ dysfunction, and gut microbiota disturbances. Inhibiting the pyroptosis pathway by nanosystems represents a potential therapeutic strategy for the treatment of sepsis. However, current pharmacological interventions primarily focus on blocking reactive oxygen species (ROS)/NOD-like receptor pyrin domain-containing 3 (NLRP3)/Caspase-1-based pyroptosis rather than lipopolysaccharide (LPS)-triggered pyroptosis. Besides, given the importance of microbiota disturbances in a second wave of cytokine storms, the assessment of the composition of intestinal flora after treatment was also missing. Herein, picroside II-encapsulated, palmitic acid-modified nanoformulations were prepared as a pyroptosis modulator to inhibit cytokine release syndrome, accompanied by reprogramming the composition of intestinal flora. Results demonstrated that the modification of palmitic acid on nanoformulations promotes the cellular uptake of nanoparticles via Toll-like receptor-mediated specific recognition. The sustained release of picroside II scavenged the massive reactive oxygen species, reduced the levels of inflammatory factors, and downregulated the pyroptosis-related proteins. Furthermore, the interaction between palmitic acid and Toll receptors reduced the combination site of LPS, providing a positive loop in drug delivery and inhibiting pyroptosis. Consequently, the obtained nanoformulations exerted a better antioxidant, anti-inflammatory, and antiproptosis activity than other treatment groups, thereby alleviating LPS-stimulated multiorgan damage, especially the kidney and colon. Interestingly, it also improved the abundance of intestinal flora, contributing to enhanced intestinal barrier function and improved immune system. Thus, palmitic acid-anchored, picroside II-encapsulated nanoformulations potentiated a systematic and desirable therapeutic outcome in sepsis treatment.