Time-Resolved Small-Angle X-ray Scattering from Cubosomes and Applications in Drug Delivery

Cubic liquid crystalline lipid nanoparticles, commonly known as cubosomes, have gained

significant attention as drug delivery systems due to their unique advantages. Unlike lipid

vesicles, cubosomes function as highly organized three-dimensional (3D) structures with

much greater internal surface area. Their architecture is simultaneously capable of

encapsulating oil-soluble drugs within their lipid bilayers and water-soluble drugs with high

molecular weight in the aqueous channel compartments. The efficacy of these nanocarriers

depends not only on their static structure but on their dynamic response to biological stimuli

and the kinetic pathways of their formation [1,2]. In this presentation, we will discuss the

application of synchrotron Small-Angle X-ray Scattering (SAXS) as a premier tool for the

structural characterization of complex self-assembled drug delivery systems. We will focus

specifically on time-resolved SAXS (TR-SAXS), which allows us to capture the structural

evolution of cubosomes with millisecond precision [3,4]. I will highlight studies on the "earliest

stages" of tetrahedral nanochannel formation and the transition of unilamellar vesicles into

hierarchical cubic architectures. Furthermore, we will present the design of stimuli-responsive

cubosomes [5,6], especially those engineered with pH-sensitive shells or those undergoing

lipid-composition-triggered transitions. Using real-time SAXS data, we demonstrate how these

nanostructures respond to environmental changes in biomimetic media, providing a

mechanism for the controlled release of diverse payloads, including neuroprotective peptides,

proteins, and anti-cancer drugs. Finally, my talk will address the future of the field, including

the integration of laser-driven ultrafast X-ray sources and the role of high-repetition-rate

detectors in pushing the boundaries of macromolecular crystallography and nanoparticle

dynamics.