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
  • 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.