2. Academic Validation
  3. Brain Nucleic Acid Delivery and Genome Editing via Focused Ultrasound-Mediated Blood-Brain Barrier Opening and Long-Circulating Nanoparticles

Brain Nucleic Acid Delivery and Genome Editing via Focused Ultrasound-Mediated Blood-Brain Barrier Opening and Long-Circulating Nanoparticles

  • ACS Nano. 2024 Sep 3;18(35):24139-24153. doi: 10.1021/acsnano.4c05270.
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,  Han Seok Ko 5 6,  Amir Manbachi 3 10,  Justin Caplan 3,  Richard J Price 11,  Betty Tyler 3,  Jung Soo Suk 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Neurosurgery, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.
  • 2 Medicine Institute for Neuroscience Discovery (UM-MIND), School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.
  • 3 Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.
  • 4 Department of Chemical and Biomolecular Engineering, School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.
  • 5 Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.
  • 6 Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.
  • 7 Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States.
  • 8 Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, United States.
  • 9 Department of Ophthalmology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21231, United States.
  • 10 Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States.
  • 11 Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, Virginia 22904, United States.
PMID: 39172436 DOI: 10.1021/acsnano.4c05270
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.

Keywords

biodegradable polymer; blood–brain barrier; brain gene therapy; long-circulating nanoparticle; systemic nucleic acid delivery.

Figures