PEGylated retinoate prodrug self-assembled nanomicelles loaded with triptolide for targeting treatment of rheumatoid arthritis and side effect attenuation.

Triptolide (TP, an active ingredient from Tripterygium wilfordii) demonstrates significant efficacy in treating rheumatoid arthritis, but its low bioavailability and multi-organ toxicity limit its application. Herein, we developed a PEGylated retinoate self-assembled nanomicelles (FA-TP@VA NPs) modified with folic acid (FA) for inflammatory macrophage-targeted delivery of TP. FA-TP@VA NPs showed an appropriate size (192.70 ± 4.37 nm), good physical stability and high drug loading (79.83 ± 5.11 % for retinoate prodrug and 6.78 ± 0.13 % for TP). FA-TP@VA NPs exhibited high cellular uptake in M1 macrophages via folate-receptor pathway, thereby inhibiting their growth. Compared with TP, FA-TP@VA NPs could effectively inhibit synovitis and erosion of bone and reduce swelling and deformation of paws by downregulation of the levels of IL-1β, IL-6, and TNF-α. In ICA mice, FA-TP@VA NPs could enhance drug-specific enrichment in inflamed joints, effectively suppress hepatic oxidative stress and reduce systemic toxicity induced by TP. Overall, FA-TP@VA NPs are a facile, carrier-free, and promising strategy for the precise treatment of rheumatoid arthritis and synergetic attenuation of side effect.