Intranasal delivery of pApoE2 via penetratin-mannose multi-functionalized chitosan polymeric micelles to the brain: Reduced total tau and phosphorylated tau burden in transgenic Alzheimer's mouse model

• Published in: International journal of biological macromolecules Vol. 310; no. Pt 4; p. 143542
• Main Authors: Gothwal, Avinash, Muolokwu, Chinenye Edith, Chaulagain, Bivek, Mahanta, Arun Kumar, Singh, Jagdish
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2025
• Subjects: Administration, Intranasal; Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Animals; astrocytes; brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Carrier Proteins - chemistry; Cell-Penetrating Peptides - chemistry; chitosan; Chitosan - chemistry; cognitive disorders; death; deoxyribonucleases; Disease Models, Animal; erythrocytes; genetically modified organisms; hexanoic acid; Humans; intranasal administration; Intranasal route; ligands; mannose; Mannose - chemistry; Mice; Mice, Transgenic; Micelles; neurons; pApoE2; peptides; Phosphorylation - drug effects; Polymeric micelles; polymers; tau Proteins - metabolism; toxicity; Intranasal route; pApoE2; Polymeric micelles
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2025.143542

The phosphorylated tau accumulation is a classical pathological hallmark of future cognitive decline and a cause of neuronal death in Alzheimer's disease (AD). In this study, we developed multi-functionalized chitosan (CS) based polymeric micelles to effectively deliver pApoE2 via intranasal administration to the brain. The CS was modified with caproic acid (CA), cell-penetrating peptide penetratin (PEN), and GLUT-1 transporter ligand mannose (MAN) for selective and enhanced delivery to the brain. The multi-functionalized Cap-g-CS-PEN-MAN polymeric micelles were ≤200 nm in size, cationic in charge, and uniformly distributed (PDI ≤ 0.3). The multi-functionalized polymeric micelles did not exhibit toxicity against bEnd.3 cells and erythrocytes up to polymer concentrations of 500 μg/mL. The Cap-g-CS-PEN-MAN /pDNA polyplex was stable against a DNase rich environment. The Cap-g-CS-PEN-MAN/pAPoE2 polyplex demonstrated elevated expression of ApoE in primary astrocytes and neurons, 9.47 ± 2.13 and 5.67 ± 2.69 ng/mg of protein, respectively. The therapeutic efficacy of the Cap-g-CS-PEN-MAN/pApoE2 polyplex was analyzed against the PS19 tauopathy mice model. Total tau burden was significantly (p ≤ 0.05) reduced by 4.09 ± 1.4 ng/mg of protein in Cap-g-CS-PEN-MAN/pApoE2 polyplex administered mice over the other groups. Phosphorylated tau pT181 level was also significantly (p ≤ 0.05) reduced in Cap-g-CS-PEN-MAN/pApoE2 polyplex administered mice over saline, pApoE2 and Cap-g-CS/pApoE2 treated groups. •Multi-functionalized chitosan-based polymeric nanocarrier for effective gene delivery to the brain.•Exploring intranasal gene delivery to the brain and finding direct access through trigeminal and olfactory nerves.•pApoE2 gene therapy is a practical therapeutic approach to reduce tau anomaly in tauopathy mice.