TY - JOUR
T1 - Brain Nucleic Acid Delivery and Genome Editing via Focused Ultrasound-Mediated Blood-Brain Barrier Opening and Long-Circulating Nanoparticles
AU - Kwak, Gijung
AU - Grewal, Angad
AU - Slika, Hasan
AU - Mess, Griffin
AU - Li, Haolin
AU - Kwatra, Mohit
AU - Poulopoulos, Alexandros
AU - Woodworth, Graeme F.
AU - Eberhart, Charles G.
AU - Ko, Han Seok
AU - Manbachi, Amir
AU - Caplan, Justin
AU - Price, Richard J.
AU - Tyler, Betty
AU - Suk, Jung Soo
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/9/3
Y1 - 2024/9/3
N2 - 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.
AB - 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.
KW - biodegradable polymer
KW - blood-brain barrier
KW - brain gene therapy
KW - long-circulating nanoparticle
KW - systemic nucleic acid delivery
UR - http://www.scopus.com/inward/record.url?scp=85201926714&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85201926714&partnerID=8YFLogxK
U2 - 10.1021/acsnano.4c05270
DO - 10.1021/acsnano.4c05270
M3 - Article
C2 - 39172436
AN - SCOPUS:85201926714
SN - 1936-0851
VL - 18
SP - 24139
EP - 24153
JO - ACS Nano
JF - ACS Nano
IS - 35
ER -