Luteolin-loaded nanocomposites target microglia for sepsis-associated encephalopathy therapy via intranasal delivery

Sepsis-associated encephalopathy (SAE) is a neurological dysfunction resulting from sepsis, with neuroinflammation identified as a key pathogenic mechanism. Luteolin (LUT) is a dietary polyphenol that possesses considerable therapeutic potential. However, its application is hindered by poor aqueous solubility, low absorption, and rapid metabolism. To address these challenges, we developed luteolin-loaded lactoferrin-chondroitin sulfate nanoparticles (LUT-LF-CS NPs) to enhance the bioavailability of LUT and evaluate its efficacy in alleviating neuroinflammation in SAE. The optimized LUT-LF-CS NPs exhibited a uniform particle size of 45.9 nm and an encapsulation efficiency of 71.73 %. These nanocomposites demonstrated excellent cytocompatibility and enhanced the intrinsic antioxidant and anti-inflammatory activities of LUT. Furthermore, they facilitated cellular uptake in microglia through CD44 receptor-mediated endocytosis, enabling effective drug delivery to the cerebral cortex after intranasal administration. Mechanistically, LUT-LF-CS NPs promoted the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype while inhibiting the TLR4/MyD88/NF-κB signaling pathway. In conclusion, LUT-LF-CS NPs significantly enhance the neuroprotective effects of LUT, positioning them as a promising therapeutic strategy for SAE.