Cyclic-AMP-response element-binding protein (CREB) is a leucine zipper class transcription factor that is activated through phosphorylation. Ample CREB phosphorylation is required for neurotrophin expression, which is of key importance for preventing and regenerating neurological disorders, including the sequelae of long COVID syndrome. Here we created lipid-peptide nanoassemblies with different liquid crystalline structural organizations (cubosomes, hexosomes, and vesicles) as innovative nanomedicine delivery systems of bioactive PUFA-plasmalogens (vinyl ether phospholipids with polyunsaturated fatty acid chains) and a neurotrophic pituitary adenylate cyclase-activating polypeptide (PACAP). Considering that plasmalogen deficiency is a potentially causative factor for neurodegeneration, we examined the impact of nanoassemblies type and incubation time in an in vitro Parkinson's disease (PD) model as critical parameters for the induction of CREB phosphorylation. The determined kinetic changes in CREB, AKT, and ERK-protein phosphorylation reveal that non-lamellar PUFA-plasmalogen-loaded liquid crystalline lipid nanoparticles significantly prolong CREB activation in the neurodegeneration model, an effect unattainable with free drugs, and this effect can be further enhanced by the cell-penetrating peptide PACAP. Understanding the sustained CREB activation response to neurotrophic nanoassemblies might lead to more efficient use of nanomedicines in neuroregeneration.

Extreme Light Infrastructure ERIC CZ 25241 Dolni Brezany Czech Republic

Institute of Rheological Functions of Food 2241 1 Kubara Hisayama cho Kasuya gun Fukuoka 811 2501 Japan

Keylab Electron and Optical Microscopy Bavarian Polymerinstitute University of Bayreuth Universitätsstrasse 30 D 95440 Bayreuth Germany

Université Paris Saclay CNRS Institut Galien Paris Saclay F 91400 Orsay France

Wenzhou Institute University of Chinese Academy of Sciences No 1 Jinlian Road Longwan District Wenzhou Zhejiang 325001 China

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Lipid and Transcriptional Regulation in a Parkinson's Disease Mouse Model by Intranasal Vesicular and Hexosomal Plasmalogen-Based Nanomedicines