Matrix metalloproteinase-sensitive size-shrinkable liposomes targeting activated macrophages for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by inflammation, swelling, pain, and cartilage and bone destruction. Exploiting the pathophysiological characteristics of matrix metalloproteinases (MMPs), which are enzymes overexpressed at the inflammation site in RA, has resulted in the development of inflammation-responsive drug delivery vectors. We here prepared a multifunctional microenvironment-responsive liposome with MMP-responsive and particle-size-shrinking properties to target macrophages at inflammation sites. In this liposome, triptolide (TP) was encapsulated in a biofilm-like bilayer with mannose-conjugated DSPE-PEG2000 as the targeting molecule and the enzyme-sensitive peptide PVGLIG as the linker arm connecting DSPE-PEG5000, which formed a hydrated membrane envelope on the liposome surface, prolonging liposome circulation while preventing the active targeting molecule from binding to normal macrophages throughout the body and reducing drug accumulation in normal tissues, thereby alleviating efficacy and reducing toxic side effects. In the joint inflammation microenvironment, PVGLIG was cleaved by overexpressed MMPs, the hydration layer of PEG5000 detached, and the target ligand Man was exposed, thereby leading to Man uptake by activated macrophages and exerting an anti-RA effect. Through in vivo and in vitro evaluations, liposomes were found to effectively target inflammation sites and enrich activated macrophages. They also inhibited osteoclastogenesis and the release of inflammatory cytokines, reactive oxygen species, and MMPs. This offers a promising new strategy in which anti-inflammatory and osteoprotective effects are combined for comprehensive RA treatment.