Pep‐Lipid Cubosomes and Vesicles Compartmentalized by Micelles from Self‐Assembly of Multiple Neuroprotective Building Blocks Including a Large Peptide Hormone PACAP‐DHA

Abstract Structural control over design and formation of self‐assembled nanomaterials for neuroprotection and neuroregeneration is crucial for their application in nanomedicine. Here a synthetic construct of the pituitary adenylate cyclase‐activating polypeptide (PACAP38) coupled to a docosahexaenoic acid (DHA: an ω‐3 polyunsaturated fatty acid (PUFA)) is designed towards the creation of compartmentalized liquid crystalline assemblies of neuroprotective compounds. The hormone PACAP38 is a ligand of the class B PAC1 G‐protein‐coupled receptor (GPCR), whereas DHA is a lipid trophic factor. The lipidated peptide PACAP‐DHA is co‐assembled into hierarchical nanostructures elaborated from hybrid vesicle‐micelle reservoirs as well into PEGylated cubosomes composed of multiple neuroprotective building blocks. The resulting nanostructures are determined by synchrotron small‐angle X‐ray scattering (BioSAXS) and cryogenic transmission electron microscopy (cryo‐TEM). Multicompartment topologies are obtained in a two‐fold approach: (i) intriguing compartmentalized vesicles, which embed pep‐lipid micelles forming nanopatterns, and (ii) multidomain pep‐lipid cubosomes. Both kinds of topologies are favorable for sustained‐release applications in combination therapies of neurodegeneration. The organizational complexity of the scaffolds involving the lipidated high‐molecular weight peptide hormone is beyond the one that has been reached with small lipid‐like peptide surfactants.