Summary: Researchers at the University of Virginia have developed a non‑invasive method to deliver therapeutic microRNAs across the blood‑brain barrier (BBB). Using MRI‑guided focused ultrasound (FUS) together with circulating microbubbles, they transiently open tight endothelial junctions in specific brain regions so brain‑penetrating nanoparticles carrying miRNAs can enter the tumor microenvironment.
In preclinical glioblastoma models, this targeted delivery approach produced substantial intratumoral accumulation of miRNA cargo, slowed tumor progression, and extended survival. The strategy provides a flexible delivery blueprint that may translate to other brain cancers and central nervous system disorders constrained by the BBB.
Key Facts
- Multi‑gene regulation with miRNA: Unlike conventional small molecules that typically act on a single protein, therapeutic microRNAs can suppress many malfunctioning genes at once, reducing the chance that glioblastoma cells escape treatment via a single altered pathway.
- Noninvasive BBB opening with FUS: MRI‑guided focused ultrasound directs acoustic energy to a precise brain target where injected microbubbles oscillate and temporarily loosen endothelial tight junctions, allowing localized drug delivery without open surgery.
- Brain‑penetrating nanoparticle carriers: The miRNA payloads are packaged in nanoparticles engineered to move through dense brain extracellular matrix and remain long enough in the tumor microenvironment to exert therapeutic effects.
- Demonstrated preclinical efficacy: In animal glioblastoma models the combined FUS + nanoparticle + miRNA treatment increased delivery into tumors, suppressed oncogenic signaling across multiple pathways, delayed tumor growth, and prolonged survival.
- Wide translational potential: Beyond glioblastoma, this platform could enable treatments for other primary and metastatic brain tumors and for neurodegenerative disorders that are currently limited by the BBB.
Source: UVA
University of Virginia scientists have devised a promising, noninvasive strategy to target glioblastoma, the most common and lethal malignant brain tumor in adults.
Led by Roger Abounader, MD, PhD, the UVA team identified specific microRNAs capable of suppressing groups of genes that drive glioblastoma initiation and progression. They combined these miRNAs with custom brain‑penetrating nanoparticles and used MRI‑guided focused ultrasound plus microbubbles to deliver the therapeutic cargo across the BBB into tumor tissue.
“This method gives us the ability to target multiple molecules that promote tumor growth — including targets for which no drugs currently exist — in a single, coordinated therapy,” said Abounader, professor at UVA’s School of Medicine and member of the Comprehensive Cancer Center and Center for RNA Science and Medicine. The team aims to advance these findings toward future clinical trials for glioblastoma and other brain tumors.
Treating Glioblastoma
Glioblastoma is an aggressive brain cancer that infiltrates normal brain tissue, making complete surgical removal impossible and contributing to a poor prognosis. The blood‑brain barrier further limits treatment options by preventing most drugs from reaching tumor cells. Standard care — maximal safe resection followed by radiation and chemotherapy — offers only modest improvements in survival.
Delivering miRNAs directly to the tumor is intended to suppress several faulty genes at once and thereby slow or halt tumor growth without the toxicity of administering multiple conventional drugs. Focused ultrasound, guided by MRI, temporarily opens the BBB by causing injected microbubbles to oscillate within cerebral vessels. This brief window allows nanoparticle carriers bearing miRNAs to pass into targeted regions of brain tissue.
In laboratory experiments and animal models, the UVA team observed slowed tumor growth and extended survival after treatment with selected miRNAs packaged into brain‑penetrating nanoparticles and delivered via FUS. While additional research is required before human trials, these results support broader investigation of miRNA delivery for brain cancer and other neurological diseases.
“This platform could have broad applications across brain diseases,” Abounader said. “Progress will depend on sustained investment in basic and translational research to move promising strategies from the lab into clinical testing.”
Focused Ultrasound at UVA
UVA was an early adopter of focused ultrasound research and maintains a robust program exploring its therapeutic potential. UVA and the Focused Ultrasound Foundation co‑founded the Focused Ultrasound Immuno‑Oncology (FUSION) Center to study how focused ultrasound can enhance cancer immunotherapy, with the long‑term goal of improving cancer care.
UVA Comprehensive Cancer Center and the Manning Institute for Biotechnology support translational research and statewide clinical trial networks to accelerate development and patient access to new therapies. UVA’s Comprehensive Cancer Center holds the National Cancer Institute’s “comprehensive” designation for excellence in patient care and research.
Findings Published
Abounader and colleagues reported their discovery and preclinical results in JCI (Journal of Clinical Investigation). The paper describes identification of regulatory miRNAs and the therapeutic delivery approach that inhibited tumor growth and extended survival in mice.
The research team includes Shekhar Saha, Ying Zhang, Myron K. Gibert Jr., Collin Dube, Farina Hanif, Elizabeth Qian Xu Mulcahy, Sylwia Bednarek, Yunan Sun, Pawel Marcinkiewicz, Xiantao Wang, Gijung Kwak, Ahsan H. Polash, Haolin Li, Kadie Hudson, Manikarna Dinda, Tapas Saha, Matthew McCord, Fadila Guessous, Nichola Cruickshanks, Rossymar Rivera Colon, Lily Dell’Olio, Rajitha Anbu, Wenjie Liu, Songy Choi, Benjamin Kefas, Pankaj Kumar, Alexander L. Klibanov, David Schiff, Jung Soo Suk, Justin Hanes, Jamie Mata, Markus Hafner and Roger Abounader. The scientists report no financial conflicts of interest.
Funding: This work was supported by the National Cancer Institute (grants U01 CA220841 and P30 CA044579), the National Institute of Neurological Disorders and Stroke (grants R01 NS122222 and R21 NS122136), a UVA Comprehensive Cancer Center pilot grant, the Schiff Foundation, the Ben and Catherine Ivy Foundation, and the Focused Ultrasound Foundation.
Key Questions Answered:
A: Glioblastoma cells infiltrate healthy brain tissue, preventing complete surgical removal. The blood‑brain barrier blocks the majority of small‑molecule drugs and nearly all large macromolecular therapies, so many potential treatments cannot reach tumor cells at effective concentrations.
A: MRI‑guided focused ultrasound concentrates low‑frequency sound waves on a precise brain target. Injected microbubbles in the bloodstream oscillate in response to the ultrasound, gently separating endothelial cells for a short period and creating a reversible, localized opening that permits drug entry without lasting tissue damage.
A: Traditional drugs usually inhibit a single protein or pathway, which tumors can often bypass. A single miRNA can target multiple mRNA transcripts simultaneously, suppressing several redundant pathways that drive tumor growth and reducing the likelihood of rapid resistance through single‑gene changes.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by editorial staff.
- Additional context was added by the publication’s team.
About this brain cancer and neurotech research news
Author: Josh Barney
Source: UVA
Contact: Josh Barney – UVA
Image: Image credited to Neuroscience News
Original Research: Open access. “Discovery and therapeutic delivery of microRNAs targeting deregulated glioblastoma pathways inhibits tumor growth in mice” by Shekhar Saha et al., JCI. DOI: 10.1172/JCI195639
Abstract
Discovery and therapeutic delivery of microRNAs targeting deregulated glioblastoma pathways inhibits tumor growth in mice
Glioblastoma is a lethal primary brain tumor with limited improvements in patient survival despite surgery, chemotherapy, and radiation. The disease commonly features simultaneous deregulation of many genes, which has limited the impact of single‑target molecular therapies. Targeting multiple deregulated molecules is likely necessary for improved outcomes, but combining many drugs increases toxicity and is often impractical.
The authors hypothesized that miRNAs — small regulatory RNAs that downregulate mRNA — could simultaneously inhibit several deregulated genes in glioblastoma. Using PAR‑CLIP screening, analysis of TCGA data, and a ranking algorithm to prioritize miRNA therapeutic potential, they identified regulatory miRNAs that target multiple dysregulated pathways. They selected tumor‑suppressor miR‑340 and miR‑382 and the oncogenic miR‑17, demonstrating these miRNAs affect cell proliferation, survival, invasion, and in vivo tumor growth.
To deliver these miRNAs therapeutically, the team combined brain‑penetrating nanoparticles with MRI‑guided focused ultrasound and microbubbles, successfully inhibiting established tumor growth and extending survival in mice. The combined delivery strategy represents a promising path toward clinical translation of miRNA‑based therapies for glioblastoma and related cancers.