Focused ultrasound-mediated blood-brain barrier opening reshapes plasma extracellular vesicle size distribution without elevating concentration in glioblastoma patients
Abstract
Background: Focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) is hypothesized to enhance liquid biopsy by facilitating the release of tumor material into the circulation. This study aimed to evaluate the impact of MR-guided FUS-BBBO on plasma extracellular vesicle (EV) concentrations and size distributions, alongside cell-free DNA (cfDNA) profiles, to determine the clinical efficacy of this approach in glioblastoma (GB) patients.
Methods: We performed 14 MR-guided FUS-BBBO procedures in patients with GB with blood sampling 1 h before and 1 h after sonication. Plasma EVs were isolated by size-exclusion chromatography and quantified by tunable resistive pulse sensing technology. cfDNA concentration and fragment profiles were assessed using fluorometric and electrophoretic methods.
Results: EV concentration showed no consistent change after FUS-BBBO, with marked inter-patient and inter-procedure heterogeneity. In contrast, EV size displayed a reproducible diameter reduction of ∼8-10 nm, driven predominantly by contraction of the upper tail of the size distribution, indicating selective modulation of larger vesicle subpopulations. cfDNA concentrations and fragmentation showed a heterogeneous pattern, with occasional patient-specific increases. Exploratory analyses revealed no significant associations between biomarker changes and procedural parameters except for treated volume.
Conclusions: Our findings challenge the assumption that clinical BBBO uniformly increases biomarker abundance. The consistent shift toward smaller EVs suggests a selective modulation rather than an increased release. While BBBO may enhance the detectability of analytes that poorly cross the BBB, this may not apply to EVs, which are able to traverse the BBB under physiological conditions, further supporting their value as liquid-biopsy substrates in neuro-oncology. Future studies integrating clinical data with mechanistic models are necessary to refine FUS-enhanced diagnostic strategies.
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BibTeX
@article{bene2026focused,
title = {{Focused ultrasound-mediated blood-brain barrier opening reshapes plasma extracellular vesicle size distribution without elevating concentration in glioblastoma patients}},
author = {Massimiliano Del Bene and Daniela Osti and Marta Bonada and Riccardo Pascuzzo and Annica Piccardi and Giovanni Carone and Lisa Meanti and Mario Stanziano and Valentina Caldiera and Carla Carozzi and Antonio Silvani and Elisa Francesca Maria Ciceri and Marina Grisoli and Giuliana Pelicci and Francesco DiMeco},
journal = {Neuro-Oncology},
year = {2026},
month = jul,
doi = {10.1093/neuonc/noag155},
url = {https://doi.org/10.1093/neuonc/noag155},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Focused ultrasound-mediated blood-brain barrier opening reshapes plasma extracellular vesicle size distribution without elevating concentration in glioblastoma patients
AU - Massimiliano Del Bene
AU - Daniela Osti
AU - Marta Bonada
AU - Riccardo Pascuzzo
AU - Annica Piccardi
AU - Giovanni Carone
AU - Lisa Meanti
AU - Mario Stanziano
AU - Valentina Caldiera
AU - Carla Carozzi
AU - Antonio Silvani
AU - Elisa Francesca Maria Ciceri
AU - Marina Grisoli
AU - Giuliana Pelicci
AU - Francesco DiMeco
PY - 2026
DA - 2026/07/14
JO - Neuro-Oncology
DO - 10.1093/neuonc/noag155
UR - https://doi.org/10.1093/neuonc/noag155
AB - Background: Focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) is hypothesized to enhance liquid biopsy by facilitating the release of tumor material into the circulation. This study aimed to evaluate the impact of MR-guided FUS-BBBO on plasma extracellular vesicle (EV) concentrations and size distributions, alongside cell-free DNA (cfDNA) profiles, to determine the clinical efficacy of this approach in glioblastoma (GB) patients. Methods: We performed 14 MR-guided FUS-BBBO procedures in patients with GB with blood sampling 1 h before and 1 h after sonication. Plasma EVs were isolated by size-exclusion chromatography and quantified by tunable resistive pulse sensing technology. cfDNA concentration and fragment profiles were assessed using fluorometric and electrophoretic methods. Results: EV concentration showed no consistent change after FUS-BBBO, with marked inter-patient and inter-procedure heterogeneity. In contrast, EV size displayed a reproducible diameter reduction of ∼8-10 nm, driven predominantly by contraction of the upper tail of the size distribution, indicating selective modulation of larger vesicle subpopulations. cfDNA concentrations and fragmentation showed a heterogeneous pattern, with occasional patient-specific increases. Exploratory analyses revealed no significant associations between biomarker changes and procedural parameters except for treated volume. Conclusions: Our findings challenge the assumption that clinical BBBO uniformly increases biomarker abundance. The consistent shift toward smaller EVs suggests a selective modulation rather than an increased release. While BBBO may enhance the detectability of analytes that poorly cross the BBB, this may not apply to EVs, which are able to traverse the BBB under physiological conditions, further supporting their value as liquid-biopsy substrates in neuro-oncology. Future studies integrating clinical data with mechanistic models are necessary to refine FUS-enhanced diagnostic strategies.
SN - 1522-8517
SN - 1523-5866
ER -