Inflammation-targeted nanoaggregates encapsulated triptolide and hyperoside for M2 macrophage repolarization and...

M1 macrophages are pivotal in rheumatoid arthritis (RA) pathogenesis, accompanied by releasing pro-inflammatory cytokines and reactive oxygen species (ROS). As a traditional anti-RA herbal ingredient, triptolide (TP) exerts potent anti-inflammatory effects via M1 macrophage modulation, but is clinically limited by poor solubility, ‌elevating ROS and systemic toxicity. Herein, we synthesized a β-cyclodextrin-grafted poly-L-glutamic acid copolymer, forming nanoaggregates (NPS) loaded with TP and hyperoside (HYP, a potent antioxidant) via host-guest interactions for RA treatment. The NPS exhibit a suitable particle size (150 nm), excellent stability and high encapsulation efficiency of 93.77% for HYP, and 86.98% for TP. NPS can selectively target M1 macrophages through HYP's galactose residues, exerting strong anti-inflammatory effects via M1-to-M2 macrophage polarization. Thereinto, HYP mitigates both RA-associated and TP-induced oxidative stress by scavenging ROS and activating antioxidant enzymes, achieving a dual effect of anti-inflammation and detoxification. In CIA mice, NPS significantly increased drug accumulation in inflamed joints relative to TP, enhancing the synergistic anti-arthritic efficacy of HYP and TP, while reducing TP-induced hepatic oxidative stress and elevating plantar pain thresholds. Overall, NPS is a promising M1 macrophage-targeted nanoaggregate for precise RA therapy and adverse effect reduction, which may improve clinical translatability of TP.