Multilayer lipid vesicles loaded with deoxyribonuclease 1 for the degradation of neutrophil extracellular traps in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent immune cell infiltration and synovial inflammation. Inflammatory stimuli recruit and trigger neutrophils to release neutrophil extracellular traps (NETs), which exacerbate joint inflammation and promote cartilage destruction. While deoxyribonuclease 1 (DNase 1) can degrade the DNA backbone of NETs, its therapeutic potential is hindered by rapid systemic clearance and poor bioavailability. To address these limitations, we develop multilayer lipid vesicles (MLVs) encapsulating DNase 1 (DMLVs) for NET degradation in RA. Compared with conventional monolayer lipid vesicles (LVs), DMLVs demonstrated enhanced stability and prolonged circulation time. In addition, the multilayer structure enabled sustained release of cargo, significantly extending DNase 1 retention at arthritic sites. In vivo studies confirmed that DMLVs effectively degrade NETs within the joint cavity, reducing cartilage erosion in a collagen-induced arthritis (CIA) mouse model. Furthermore, this therapeutic strategy downregulated pro-inflammatory cytokine levels and suppressed immune cell recruitment, leading to a marked reduction in joint swelling. This work establishes DMLVs as an effective nanoplatform for NETs-targeted RA therapy while demonstrating their advantages over conventional LVs in drug delivery efficiency and therapeutic outcomes. STATEMENT OF SIGNIFICANCE: This study presents a multilayer lipid vesicles (MLVs) system encapsulating DNase 1 (DMLVs) for targeted degradation of neutrophil extracellular traps (NETs) in rheumatoid arthritis (RA). Unlike conventional vesicles, DMLVs offer enhanced stability, extended circulation, and sustained enzyme release. These features enable efficient NETs clearance, reduction of inflammation, and protection against cartilage damage in arthritic joints. The work is significant because it introduces a nanoplatform that overcomes the limitations of free DNase 1 therapy and provides a promising strategy for treating autoimmune diseases driven by NETs. This research will interest readers in nanomedicine and inflammatory disease management.