Engineered Drug-Amphiphile Conjugate Nanoparticles for Targeted Inhibition of AQP4-Mediated NLRP3 Inflammasome Signaling in Collagen-Induced Rheumatoid Arthritis

Aquaporins (AQPs) are transmembrane proteins that transport water, small solutes, and molecules across cell membranes. Studies have reported the role of AQPs in the activation, migration, and proliferation of immune cells, thus modulating the pathogenesis of autoimmune disease. In joints, the enhanced AQP4 expression exaggerates pathological changes like hydrarthrosis, acidosis, and hyperosmotic stress-inducing dysfunction of the articular chondrocytes, leading to articular cartilage destruction in collagen-induced arthritis (CIA). Acetazolamide (AZM), a sulfonamide carbonic anhydrase inhibitor of AQP4, reversibly decreases water permeability through AQP4 and is a potential molecule for targeting AQP4 in the CIA. However, its low solubility and low bioavailability limit its therapeutic effectiveness. Therefore, in this study, we have synthesized a polyphenol drug (gallic acid) (GA) and an amphiphile (glycerol monostearate) (GMS) conjugate to self-assemble into nanoparticles and encapsulated with AZM. Apart from AZM, GA is known for its antioxidant and anti-inflammatory properties. Therefore, intra-articular injection of AZM@GA-GMS NPs efficiently downregulates the expression of AQP4 and associated NLRP3 inflammasome activation. Moreover, the NPs are cytocompatible and showed enzyme-responsive drug release and thus offer a promising therapeutic strategy for RA by inhibiting AQP4-mediated inflammatory pathways. This opens up an avenue for treatment for RA.