Paeoniflorin-loaded pH-sensitive liposomes alleviate synovial inflammation by altering macrophage polarity via STAT signaling.

Macrophage polarization plays a prominent role in the pathogenesis of rheumatoid arthritis (RA) and could be regulated by natural extracts paeoniflorin (Pae) but with low bioavailability. In the present study, Pae-loaded liposomes (Pae-LS) with co-conjugation of folate and PEG were prepared for the improvement of therapeutic benefits. We evaluated biophysical characterizations of Pae-LS and macrophage uptake of liposomes, as well as gain insight into whether Pae-LS can improve synovial inflammation in CIA rats and how Pae-LS promoted RAW 264.7 macrophages phenotype switch. We found that Pae-LS showed physical stability, sustained release, long circulation, pH-responsive properties, and higher uptake by active macrophages than free Pae. Furthermore, Pae-LS could repress STAT1 phosphorylation to reduce the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and iNOS expression, as well as lead to a marked increase in anti-inflammatory cytokine (IL-10) and CD206 levels via elevated p-STAT6. In contrast to free Pae, Pae-LS treatment was more effective in alleviating synovial inflammation and hyperplasia in the ankle joint of CIA rats. Our study revealed Pae-LS could effectively suppress synovial inflammation of CIA rats by regulating macrophage polarization via STAT signaling and had the potential for RA treatment as liposome delivery carriers systems.