“Lego-Brick”-Style Supramolecular Self-Assembly for Naringin–Chlorogenic Acid–Glucosylrutin Carrier-Free Nanoparticles: Self-Assembly Mechanism, Release Behavior, and Anti-Inflammatory Activity

Abstract

Naringin (NG), a citrus flavonoid with anti-inflammatory properties, suffers from low solubility, limiting the full realization of its health benefits. Inspired by the modular assembly concept of “Lego-bricks”, this study constructed naringin–chlorogenic acid–glucosylrutin carrier-free nanoparticles (NCGN) with high apparent co-assembly efficiency (95.38 ± 0.77%) and loading capacity (32.54 ± 0.47%) through supramolecular self-assembly, leading to 4.6-fold increase in the aqueous solubility of NG. Investigation into the supramolecular self-assembly mechanism revealed that the process was primarily driven by π–π stacking between aromatic rings, with synergistic effects from hydrogen bonding and van der Waals forces. Notably, the release efficiency of NCGN reached 93.4% in simulated solutions, which was predominantly driven by non-Fickian diffusion and skeletal dissolution. The biocompatibility evaluation revealed non-toxicity within the tested concentration range of 100 μg/mL, indicating good biocompatibility. In vitro anti-inflammatory experiments showed that NCGN exhibited significantly reduced levels of IL-6 and TNF-α, demonstrating its potent anti-inflammatory activity.