Therapeutic Effects of Dietary Vesicle-Like Nanoparticles on NLRP3 Inflammasome-Mediated Inflammatory Diseases

The nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome plays an essential role in mediating innate immune responses. The aberrant activation of the NLRP3 inflammasome drives the pathogenesis and progression of various inflammatory diseases, such as obesity, atherosclerosis, and Alzheimer’s disease. Therefore, the NLRP3 inflammasome has been recognized as a desirable drug target, but specific NLRP3 inflammasome-targeted medications have not become clinically available. In our studies, three different kinds of dietary vesicle-like nanoparticles (VLNs) have been found to possess potent anti-NLRP3 inflammasome functions in vitro and in vivo. Dietary VLNs are membrane-enclosed tiny vesicles isolated from foods, which contain a variety of biomolecules, including RNAs, proteins, and lipids. Dietary VLNs have emerged as a new class of agents with potential therapeutic functions. In our studies, VLNs were isolated from shiitake mushroom (S-VLNs), garlic chives (GC-VLNs), and honey (H-VLNs) respectively. In vitro studies in mouse bone marrow-derived macrophages (BMDMs) revealed that all three kinds of dietary VLNs exhibit potent inhibitory effects on the NLRP3 inflammasome. Thereafter, their therapeutic effects were evaluated in different NLRP3 inflammasome-driven inflammatory diseases. S-VLNs protected the mice from D-galactosamine (GalN) and lipopolysaccharide (LPS)-triggered acute liver injury, an acute inflammatory disease mediated by the NLRP3 inflammasome. The hepatic damage and inflammation were suppressed by S-VLNs. GC-VLNs were administered to diet-induced obese mice either orally or intravenously. Both administrations improved the glucose homeostasis of obese mice and reduced obesity-associated inflammation. Furthermore, the phospholipid 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (PC(36:4), or DLPC) in GC-VLNs was identified to inhibit NLRP3 inflammasome activation. The therapeutic effects of H-VLNs were explored in the acute liver injury and aging mouse models respectively. H-VLNs curbed hepatic damage and inflammation induced by GalN/LPS. H-VLNs also alleviated hepatic inflammation, fibrosis, and carcinoma in aged mice. miR-4057 in H-VLNs was identified to inhibit NLRP3 inflammasome activation. Together, our studies have discovered three kinds of dietary VLNs containing natural inflammasome inhibitors that can be potentially utilized in combating NLRP3 inflammasome-driven diseases