Quantum chemical calculation-guided design of “Lego-brick”-style supramolecular self-assembly for constructing naringin nanorods with anti-inflammatory function

Naringin, a poorly soluble citrus flavonoid with anti-inflammatory effects, suffers from low gastrointestinal absorption due to poor solubility, limiting its bioavailability and nutritional effects. Inspired by the modular assembly concept of “Lego-brick”, this study successfully designed and constructed a novel supramolecular self-assembled nanorod through quantum chemical calculation guidance. The co-assembly units were screened from five natural products through the employment of molecular dynamics simulations, revealing that the stable and highly ordered supramolecular structure could be formed between chlorogenic acid and naringin (NG) driven by non-covalent interactions. The naringin-chlorogenic acid nanorod (NCN) exhibited extremely high encapsulation efficiency (94.6 %) and loading capacity (59.3 %). The NCN elevated the solubility of NG to 2.89 mg/mL, which is a nearly 3-fold enhancement compared with the solubility of pure NG. The self-assembly process of NCN was revealed through density functional theory calculations, which indicated that it was predominantly driven by π-π stacking interactions between aromatic rings, along with the synergistic effects of hydrogen bonding and van der Waals forces. Notably, the release ratio of NCN in simulated gastrointestinal solutions increased by 4.6 times compared to that of NG, achieving a 12 h release rate of 95.1 %, with the release mechanism governed by the synergistic control of Fickian diffusion and matrix dissolution. Furthermore, the NCN exhibited excellent biocompatibility, showing non-toxic properties for Raw 264.7 cells and the hemolysis ratio of less than 5 %. And the NCN showed excellent anti-inflammatory function, evidenced by IL-6 and TNF-α levels in its group dropping from 3074.1 pg/mL and 5109.5 pg/mL to 933.3 pg/mL and 1481.0 pg/mL, respectively. This research provides a new insight to overcome the application bottlenecks of citrus flavonoids, offering fresh insights for designing anti-inflammatory bioactive products through supramolecular nano-delivery systems. • Naringin nanorods were constructed through the inspiration from “Lego bricks”. • Self-assembly mechanism of nanorods was elucidated by quantum chemical calculations. • Release efficiency of naringin nanorods in the gastrointestinal tract was enhanced. • Naringin nanorods demonstrated excellent anti-inflammatory functions.