Improving oleoyl hyaluronan self-assembly and functional properties using zinc ions

The self-assembly of polymer-based drug carriers plays a critical role in their performance in drug delivery and targeting. In this study, we investigated the effect of various salts on the aggregation behavior of oleoyl-modified hyaluronic acid (OL-HA) and its functional properties. Structural organization was assessed by dynamic light scattering, atomic force microscopy, scanning electron cryomicroscopy, surface tension, rheology and steady-state and time-resolved fluorescence (probes pyrene, Nile red and perylene), revealing that zinc acetate promotes self-assembly compared to water and phosphate-buffered saline, forming smaller (12 vs. 24 nm) and more compact hydrophobic domains with higher microviscosity (388 vs. 35 mPa∙s in Zn(Ac)₂ compared to PBS). These structural improvements translated into a substantial increase in drug loading capacity, with curcumin showing a 20% enhancement (50.5 vs. 42.2 μg/ml) and imidazole-based antimicrobial agents up to a 45-fold improvement (miconazole content reached 386.0 μg/ml in Zn(Ac)₂ vs. 8.3 μg/ml in PBS). Beyond loading, zinc acetate remarkably boosted the biological performance of OL-HA carriers: curcumin penetration into skin increased by 69%, antifungal-loaded systems demonstrated efficient skin permeation (reaching 43% for bifonazole), formed distinct inhibition zones against Candida albicans (zone diameter up to 5.4 ± 0.6 mm) and prevented Aspergillus brasiliensis colonization (up to 0% coverage), and zinc acetate-containing formulation achieved the greatest wound closure of 84.5 ± 10.3% in keratinocyte scratch assays. This study establishes a structure-property-function relationship for OL-HA and highlights zinc acetate as a simple yet powerful excipient for tuning the self-assembly and efficacy of HA-based nanocarriers.