Construction and evaluation of injectable enzyme-crosslinked emodin liposome nanohydrogel: Mechanistic study on inhibiting pyroptosis for the treatment of rheumatoid arthritis

Injectable nanohydrogel enabled localized and sustained intra-articular delivery. • GLP hydrogel prolonged joint retention and enabled sustained local drug exposure. • GLP hydrogel alleviated synovial inflammation and cartilage damage in CIA rats. • GLP hydrogel suppressed NF-κB/NLRP3-driven pyroptosis with good in vivo safety. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation. To overcome the limitations of conventional therapies, including poor bioavailability, insufficient target specificity, and cumulative systemic toxicity, this investigation delineates the design and fabrication of an enzymatically cross-linked hydrogel scaffold derived from a gelatin-gallic acid (GGA) graft copolymer, designated as GGA@Lipo@EMO (GLP), for the encapsulation of emodin (EMO)-loaded liposomal nanoparticles. This advanced delivery platform facilitates localized sustained release and precise intra-articular drug delivery. Rheological analysis, scanning electron microscopy (SEM), and proton nuclear magnetic resonance ( 1 H NMR) confirmed its injectability, interconnected porous structure, and controlled release behavior. The Network pharmacology analyses, in vitro cellular experiments, and in vivo studies using collagen-induced arthritis (CIA) rat models collectively demonstrate that the GLP hydrogel effectively inhibits the nuclear factor-κB (NF-κB) signaling pathway and NOD-like receptor protein 3 (NLRP3) inflammasome activation, thereby blocking cysteine–aspartic acid protease-1 (caspase-1)/gasdermin D (GSDMD)-mediated pyroptosis. This results in significant downregulation of key inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18), thereby mitigating inflammatory cell infiltration and cartilage degradation. The GLP hydrogel exhibits substantial therapeutic efficacy and favorable biosafety, offering a new approach for localized therapy of RA. Download: Download high-res image (211KB) Download: Download full-size image