# Nanostructured Lipid Carriers as Physicochemical Modulators of Complex Natural Extracts: Release Behavior and Bile-Induced Remodeling in Biorelevant Media

## TL;DR

This study explores how nanostructured lipid carriers can improve the release and accessibility of a complex natural product, propolis, in simulated digestive conditions.

## Contribution

The study introduces a novel NLC platform to modulate the release of propolis and reveals how bile components influence its accessibility through dynamic remodeling.

## Key findings

- NLCs achieved high encapsulation efficiency and stability for propolis over 90 days.
- Bile components in intestinal media caused pH- and composition-dependent morphological changes in NLCs.
- Fasted-state conditions increased propolis accessibility without full carrier disruption.

## Abstract

Propolis is a chemically complex natural product with recognized antioxidant potential, but its compositional heterogeneity and poor aqueous solubility complicate formulation and interpretation of in vitro release behavior. In this study, a nanostructured lipid carrier (NLC) based on Gelucire® 44/14 was developed as a physicochemical platform to modulate the accessibility of a selected Chilean ethanolic propolis extract. Propolis extracts from different origins were first screened using complementary antioxidant assays (DPPH, ABTS, ORAC, FRAP), leading to the selection of the Peñaflor extract, which exhibited the highest phenolic content (~41 mg GAE/g) and antioxidant capacity. The selected extract was incorporated into NLCs with encapsulation efficiencies above 90%, a narrow size distribution (~200 nm), and high stability over 90 days. Under simple aqueous conditions, propolis release remained limited (<15% over 6 h), consistent with diffusion- and partition-controlled transport. In simulated gastrointestinal media containing bile components, pronounced pH- and composition-dependent effects were observed. While fed-state intestinal conditions induced extensive morphological remodeling without increasing the analytically accessible fraction (<3% at 4 h), fasted-state intestinal media promoted a higher accessible fraction (~14% within 1 h) without complete carrier disruption, as confirmed by transmission electron microscopy. Preliminary cytocompatibility studies in HepG2 cells showed acceptable viability at 10–40 µg/mL and concentration-dependent effects at higher doses. Overall, this work demonstrates that bile components modulate propolis accessibility through dynamic partitioning and colloidal reorganization rather than simple carrier breakdown, providing a physicochemical framework for future digestion and absorption studies.