Lipid Phase Organization Controls Drug Partitioning and Release Across Lipid Nanocarriers

Abstract

Understanding how lipid organization governs drug incorporation and release across nanocarrier platforms remains a central challenge in the rational design of lipid-based delivery systems. Here, lipid nanoparticles (LNP), liposomes (LIP), solid lipid nanoparticles (SLN), and nanostructured lipid carriers (NLC) were systematically compared to establish direct relationships between lipid composition, local structural order, and release behavior. Dexamethasone was employed as a model lipophilic probe to investigate molecular partitioning across these distinct lipid environments. Nanocarriers were characterized in terms of size, polydispersity, zeta potential, encapsulation efficiency (EE), and drug loading (DL), while lipid dynamics were resolved by spin-label electron spin resonance (ESR) using depth-sensitive probes. In vitro release profiles were obtained at 4 and 37 °C to evaluate temperature-dependent permeability. SPC-based liposomes exhibited the highest incorporation (EE ≈ 90%; DL ≈ 45 µmol/mol) and the lowest motional restriction, as indicated by reduced rotational correlation times and 2A|| values, and displayed the slowest release kinetics. In contrast, HSPC-based liposomes generated the most ordered lipid environments, with the highest ESR-derived motional parameters, exceeding those observed for SLN and LNP, and showed rapid release at 37 °C but strong retention at 4 °C, indicating pronounced thermal sensitivity. SLN, NLC, and LNP exhibited lower incorporation (EE < 35%) and intermediate motional restriction, converging toward less favorable environments for drug accommodation despite their distinct supramolecular structures. Across all systems, encapsulation and release behavior correlated consistently with ESR-derived descriptors of lipid mobility and order rather than with nanocarrier class. These findings demonstrate that the physicochemical state of the lipid phase-defined by composition, packing, and dynamic heterogeneity-governs molecular accommodation and diffusion. This work establishes a direct experimental framework linking lipid organization to functional performance and provides quantitative descriptors to guide the rational design of lipid nanocarriers beyond conventional structural classification.