Mechanistic Insights into Tannic Acid–Polyethylene Glycol-Induced Self-Assembly of Nobiletin: From Molecular Binding to Enhanced Bioavailability

Bioactive components, especially hydrophobic functional molecules, have inspired various nanobiotechnology approaches to stabilize and further realize their biological functions, particularly in vivo delivery. Desirable features of a delivery system for functional molecules should possess high biocompatibility, favorable encapsulation capacity, and simple fabrication processes without requiring chemical modification of the molecule itself. Herein, we report a facile and low-cost approach, based on tannic acid-polyethylene glycol (TA-PEG)-mediated assembly, for assembling citrus-derived nobiletin into nanoparticles (i.e., NTP NPs) under aqueous conditions. The resulting multifunctional spherical NPs with long-term stability and desirable encapsulation efficacy are mostly facilitated by hydrogen bonding and π interactions, as confirmed by in-depth spectroscopic analyses. Incorporating fluorophores into NTP NPs enables the visualization of intracellular transport and biodistribution at different time points, revealing that most of these NPs achieved enhanced cellular uptake and transport efficiency and prolonged intestinal retention, comparable to that of free nobiletin. This work provides a viable strategy for the rational design of hydrophobic functional molecule nanoparticle delivery platforms tailored for diverse biological applications.