Lipid nanoparticles (LNPs) have emerged as powerful platforms for therapeutic delivery, exemplified by the global deployment of LNP-based mRNA COVID-19 vaccines. Within this broader class, lyotropic liquid crystalline nanoparticles (LLCNPs), including cubosomes, hexosomes and related non-lamellar structures, offer unique opportunities for drug delivery owing to their complex internal nanostructures. Understanding how these physicochemical and structural features influence biological interactions is central to nanotoxicology and the rational design of safe and effective nanomedicines.
We systematically investigated how the internal mesophase of LLCNPs affects cellular interactions and uptake pathways. Comparative confocal microscopy and flow cytometry studies on LNPs with distinct internal structures revealed that non-lamellar LLCNPs exhibit enhanced cellular interactions relative to liposomes. Cubosomes, in particular, exhibited uptake via direct membrane fusion, bypassing conventional endocytic pathways that often limit cytosolic delivery. For the first time, membrane fusion with mammalian plasma and endosomal membranes was visualised at the nanoscale, revealing how cubosomes can deliver cargo directly into the cytosol.
In this talk, I will illustrate the translational implications of these mechanistic insights through three case studies. First, I will discuss LNPs for mRNA delivery, focusing on how ionisable lipid chemistry influences nanoparticle structure, stability, and transfection efficiency. The performance of mRNA-LNPs loaded within a polymer microneedle array and the impact on cold chain storage requirements will be described. Second, I will summarise the design and evaluation of LLCNPs for treating bacterial infections, including tuberculosis, highlighting how nanoparticle structure and uptake pathways shape antimicrobial efficacy and biodistribution. Third, I will present LNP-based strategies for ocular disease, where tuning nanostructure and surface properties enables controlled delivery to ocular tissues while maintaining biocompatibility. Beyond advancing drug delivery applications, these studies provide mechanistic insights into how nanoscale structural features modulate biological responses, contributing to broader understanding of nanoparticle–cell interactions relevant to nanotoxicology, biodistribution, and safe nanomaterial design.