Targeted delivery of kaempferol via mannose-modified PLGA nanoparticles reprograms macrophages and ameliorates rheumatoid arthritis.

BACKGROUND

While the natural flavonoid Kaempferol (Kae) possesses promising anti-inflammatory and immunomodulatory properties for treating rheumatoid arthritis (RA), it is challenged by poor aqueous solubility and low bioavailability, which impede its targeting of key effector cells like macrophages and limit its clinical utility.

PURPOSE: To overcome Kae's pharmaceutical limitations in RA therapy, We developed mannose-modified PLGA nanoparticles (Kae-NPs) for macrophage-targeted delivery and investigated their therapeutic efficacy and underlying mechanisms.

METHODS

Integrated bioinformatic analyses of GEO datasets identified macrophage-related pathways as central to rheumatoid arthritis (RA) pathogenesis. Kae-NPs were synthesized and evaluated for their morphology, size distribution, surface charge, and drug-release profile. Cellular uptake and macrophage polarization were assessed in LPS-treated RAW264.7 cells by flow cytometry, ELISA, and immunofluorescent staining. In a collagen-induced arthritis (CIA) rat model, therapeutic efficacy and mechanisms were evaluated through small-animal imaging, micro-CT, histopathology, and serum immune profiling.

RESULTS

Kae-NPs showed uniform size (∼136 nm) and sustained release. They were efficiently internalized by macrophages and promoted M1-to-M2 polarization in vitro. In CIA rats, Kae-NPs accumulated in inflamed joints, reduced swelling, cartilage damage, and bone erosion. Mechanistically, Kae-NPs scavenged ROS, modulated cytokine production by suppressing IL-6, IL-1β and TNF-α while elevating TGF-β and IL-10, restored Treg/Th17 balance, and inhibited fibroblast-like synoviocyte (FLS) proliferation, with no systemic toxicity observed.

CONCLUSIONS

Kae-NPs enable targeted Kae delivery to joint macrophages, ameliorating RA through ROS clearance, macrophage reprogramming, and immune homeostasis restoration, offering a promising nanotherapeutic strategy.