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Liquid crystal nanoparticles (LCNPs), such as hexosomes based on an internal hexagonal phase (H_II), enhance lipid nanoparticle-mediated drug delivery by improving drug solubility, stability and absorption. LCNPs can also be tailored for specific biological environments by incorporating non-ester-linker lipids into the H_II nanostructure. In this study, we developed an H_II model system with a 90:10 phytantriol:farnesol ratio based on experimental data and conducted all-atom molecular dynamics simulations. The model remained stable across various water-to-lipid ratios, and the structural effects observed were consistent with prior experimental data. We used this model to examine the localization and interactions of antibiotics vancomycin and clarithromycin. Clarithromycin, being highly lipophilic, associated mainly with the lipid phase, while vancomycin localized at the water-lipid interface due to its amphiphilic nature. An extended H_II system with repeating units enclosed in Pluronic F127 polymers was also constructed. Simulations showed that hydrogen bonding between Pluronic F127 and water facilitated water influx into the H_II phase, causing interfacial reorganization. To investigate drug release, we performed umbrella sampling simulations. The resulting energy profiles indicated that polymer-water-lipid interactions lowered the energy barrier for vancomycin release compared to clarithromycin. This was confirmed by in vitro release studies, where vancomycin exhibited a higher release rate. Overall, this model provides molecular-level insights into drug loading, partitioning, and release from H_II systems, supporting the design of more effective drug delivery formulations.

Antibiotics are essential for treating infections and reducing risks during medical interventions. However, many commonly used antibiotics lack the physiochemical properties for an efficient oral administration when treating systemic infection. Instead, we are reliant on intravenous delivery, which presents complications outside of clinical settings. Developing novel formulations for oral administration is a potential solution to this problem. We engineered hexosome and cubosome liquid crystal nanoparticles (LCNPs) characterized by small-angle X-ray scattering and cryogenic transmission electron microscopy, and could encapsulate the antibiotics vancomycin (VAN) and clarithromycin (CLA) with high loading efficiencies. By rationally choosing stable lipid building blocks, the loaded LCNPs demonstrated excellent resilience against enzymatic degradation in an in vitro gut model LCNP stability is crucial as premature antibiotic leakage can negatively impact the gut microbiota. In screens against the representative gut bacteria Enterococcus faecalis and Escherichia coli, our LCNPs provided a protective effect. Furthermore, we explored co-administration and dual loading strategies of VAN and CLA, and demonstrated effective loading, stability and protection for E. faecalis and E. coli. This work represents a proof of concept for the early-stage development of antibiotic-loaded LCNPs to treat systemic infection via oral administration, opening opportunities for combination antibiotic therapies.

The global rise in antimicrobial resistance has created an urgent demand for novel drug delivery strategies that can improve access to antibiotics and reduce reliance on intravenous administration. Oral therapy remains the most practical route for outpatient treatment, yet many antibiotics display poor solubility, low permeability, and instability in the gastrointestinal tract, limiting their effectiveness. Lipid-based nanocarriers, particularly liquid crystal nanoparticles (LCNPs), offer structural versatility, high internal surface area, and tunable release properties that make them attractive for enabling oral delivery. 

The overall aim of this thesis was to develop LCNP-based oral formulations of clinically relevant antibiotics through an integrated approach combining molecular understanding with potential scalable manufacturing.

In the first part, antibiotic-loaded LCNPs with internal cubic and hexagonal phases were developed from non-digestible lipid building blocks and systematically evaluated for their physicochemical properties, stability in simulated intestinal fluids, and impact on representative commensal bacteria. Complementing these experimental findings, all-atom molecular dynamics simulations were employed to reveal that the studied antibiotics, clarithromycin preferentially localized within the lipid domain, whereas vancomycin resided at the lipid–water interface. Therefore, these primary results provide both experimental and molecular-level evidence for how lipid composition and nanostructure govern drug localization, stability, and release in LCNPs-based antibiotic formulations.

In the second part, the influence of internal mesophase on transepithelial permeability was investigated in intestinal models using Caco-2 cells. Compared with liposomes, non-lamellar LCNPs exhibited superior uptake via energy-independent internalization and significantly enhanced vancomycin transport across intestinal monolayers, underscoring the role of mesophase architecture in promoting oral absorption.

In the final part, a semi-solid extrusion (SSE) 3D printing platform was developed to convert vancomycin-loaded hexosomes into personalized oral tablets. LCNPs-based formulations preserved a stable hexagonal phase throughout the preparation of the printable gel, the 3D printing process, and tablet rehydration. Moreover, the printed tablets complied with European Pharmacopoeia standards for mass uniformity, drug content, and disintegration. The optimized gels displayed favorable rheological properties, ensuring precise, reproducible dosing for better patient compliance.