Inflammation-targeted nanoaggregates encapsulated triptolide and hyperoside for M2 macrophage repolarization and oxidative stress reversal in rheumatoid arthritis therapy.

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.