Size-dependent cellular association of cubosomes as nanocarriers

Cubosomes feature in the growing arsenal of lipid nanocarriers for drug delivery applications. Particle size has been shown to significantly influence the performance of vaccines and chemotherapeutics using other types of nanoparticles. However, elucidating size-property relationship with cubosomes has been challenging. The development of microfluidic preparation methodology is enabling the unravelling of size-dependent properties for these particles. In this study, we focus on studying the critical role of cubosome particle size in nano-bio interactions as nanocarriers. Using a combination of live and fixed cell imaging of three cell lines, observation of direct model-membrane interactions, and Monte-Carlo simulations, it was found that smaller cubosomes (mean diameter ∼120 nm) displayed significantly higher cellular association than larger cubosomes (∼ 260 nm). The enhanced membrane interactions of smaller cubosomes may make them more robust to challenging therapeutic delivery environments and may offer superior fusogenicity. Our study underscores the potential of size-optimized cubosomes as versatile customised nanocarriers in next-generation precision nanomedicine.