Elucidating the structure of “biogenic” cubosomes, containing biological components from Red Blood Cell-derived Extracellular Vesicles.

Lipid-based liquid crystalline nanoparticles (LCNPs), such as cubosomes and hexosomes, show great promise for drug delivery due to
their structural versatility and high fusogenicity with lipid membranes. Hybridizing LCNPs with extracellular vesicles (EVs) may
overcome challenges of synthetic nanoparticles, such as immune responses and lack of tissue targeting. We developed a microfluidic
method to integrate red blood cell-derived EVs (RBCEVs) into glycerol monooleate (GMO)-based cubosomes, leading to hybrid systems
that combine EVs’ targeting abilities with LCNPs’ drug-loading capacity. These hybrids demonstrated excellent colloidal stability
without steric stabilizers. SAXS revealed that incorporating RBCEVs into the GMO scaffold induces a phase transition from a diamond
cubic to a primitive cubic phase. However, SAXS cannot resolve the spatial arrangement of RBCEVs’ lipids and proteins, which is
critical for their biological and biomedical functions. To address this, we will leverage SANS, in combination with selective deuteration
and contrast variation, to map the distribution of RBCEVs within the hybrid system, thereby advancing biogenic LCNPs development for
drug delivery.