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

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.