l-Type amino acid transporter 1-targeting nanoparticles for antisense oligonucleotide delivery to the CNS

• Published in: Molecular therapy. Nucleic acids Vol. 35; no. 4; p. 102340
• Main Authors: Lim, Yu Na, Ryu, In Soo, Jung, Yeon-Joo, Helmlinger, Gabriel, Kim, Insun, Park, Hye Won, Kang, Hansol, Lee, Jina, Lee, Hyo Jin, Lee, Kang Seon, Jang, Ha-Na, Ha, Dae-In, Park, Junghyung, Won, Jinyoung, Lim, Kyung Seob, Jeon, Chang-Yeop, Cho, Hyun-Jeong, Min, Hyun Su, Ryu, Jin-Hyeob
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.12.2024; American Society of Gene & Cell Therapy; Elsevier
• Subjects: antisense oligonucleotide; ASO; ASO delivery; BBB; blood-brain barrier; l-type amino acid transporter 1; LAT1; LAT1-targeting nanoparticles; MT: Oligonucleotides: Therapies and Applications; NPs; Original; PEG-PLL; polyion complex micelle; LAT1-targeting nanoparticles; NPs; blood-brain barrier; MT: Oligonucleotides: Therapies and Applications; LAT1; l-type amino acid transporter 1; BBB; antisense oligonucleotide; ASO delivery; PEG-PLL; ASO; polyion complex micelle
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2024.102340

l-Type amino acid transporter 1 (LAT1)-specific ligands and polyion complexes are used as brain-specific targets to deliver RNA-based drugs across the blood-brain barrier. We characterized an LAT1-targeting antisense oligonucleotide (ASO)-encapsulated nanoparticle, Phe-NPs/ASO. A 25% density of phenylalanine effectively binds to the surface of LAT1-targeting NPs in the GL261-Luc cells, and Phe-NPs/ASO shows higher binding affinity compared to that without phenylalanine by cellular binding assay. To further characterize the blood-brain barrier-targeting effect and tissue distribution following a single-dose intravenous injection in mice, we performed in vivo biodistribution studies using fluorescence imaging. The Phe-NPs/ASOs were detected in the brain tissue 1 h post-intravenous injection at an approximately 64-fold higher ratio than that of the same ASOs administered in the absence of any NP carrier. The brain tissue delivery of ASO-loaded Phe-NPs was also confirmed in a fluorescence imaging study performed in non-human primates. These results demonstrate that Phe-NPs may successfully deliver an ASO to the brain tissue across brain regions. Phe-NPs loaded with RNA-based drugs have the potential to treat diseases of the CNS, including all forms of neurodegenerative diseases. [Display omitted] Lim and colleagues demonstrate that intravenous delivery of antisense oligonucleotide (ASO)-loaded phenylalanine-nanoparticles (Phe-NPs) targets the brain via l-type amino acid transporter 1 (LAT1), exhibiting effective ASO distribution and target gene knockdown in the brain. This LAT1-targeting Phe-NPs/ASOs provides the potential for a drug delivery application in CNS diseases.