석정수 (University of Maryland, Johns Hopkins University School of Medicine)

한빛사논문

조회72

University of Maryland, Johns Hopkins University School of Medicine

CV File 168 kb

ACS Nano, Aug 22 2024, | https://doi.org/10.1021/acsnano.4c05270 Brain Nucleic Acid Delivery and Genome Editing via Focused Ultrasound-Mediated Blood-Brain Barrier Opening and Long-Circulating Nanoparticles

Gijung Kwak ^1,2, Angad Grewal ³, Hasan Slika ³, Griffin Mess ³, Haolin Li ^1,4, Mohit Kwatra ^5,6, Alexandros Poulopoulos ⁷, Graeme F Woodworth^1,2, Charles G Eberhart ^8,9, Hanseok Ko ^5,6, Amir Manbachi ^3,10, Justin Caplan ³, Richard J Price¹¹, Betty Tyler ³, Jung Soo Suk ^1,2,3,4

¹Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.

²Medicine Institute for Neuroscience Discovery (UM-MIND), School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.

³Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.

⁴Department of Chemical and Biomolecular Engineering, School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.

⁵Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.

⁶Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.

⁷Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.

⁸Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, United States.

⁹Department of Ophthalmology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States.

¹⁰Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.

¹¹Department of Biomedical Engineering, School of Enginee

Corresponding Author : Jung Soo Suk

Abstract

We introduce a two-pronged strategy comprising focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening and long-circulating biodegradable nanoparticles (NPs) for systemic delivery of nucleic acids to the brain. Biodegradable poly(β-amino ester) polymer-based NPs were engineered to stably package various types of nucleic acid payloads and enable prolonged systemic circulation while retaining excellent serum stability. FUS was applied to a predetermined coordinate within the brain to transiently open the BBB, thereby allowing the systemically administered long-circulating NPs to traverse the BBB and accumulate in the FUS-treated brain region, where plasmid DNA or mRNA payloads produced reporter proteins in astrocytes and neurons. In contrast, poorly circulating and/or serum-unstable NPs, including the lipid NP analogous to a platform used in clinic, were unable to provide efficient nucleic acid delivery to the brain regardless of the BBB-opening FUS. The marriage of FUS-mediated BBB opening and the long-circulating NPs engineered to copackage mRNA encoding CRISPR-associated protein 9 and single-guide RNA resulted in genome editing in astrocytes and neurons precisely in the FUS-treated brain region. The combined delivery strategy provides a versatile means to achieve efficient and site-specific therapeutic nucleic acid delivery to and genome editing in the brain via a systemic route.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-29)
연구진국외 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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