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Engineered nanoparticles for systemic siRNA delivery to malignant brain tumours
Johan Karlsson1, Yuan Rui2, Kristen L Kozielski2
1Department of Biomedical Engineering and the Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. green@jhu.edu and Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD 21218, USA. searson@jhu.edu and Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Engineered nanoparticles effectively deliver siRNA across the blood-brain barrier (BBB) for brain cancer treatment. This biodegradable nanocarrier enables gene silencing in glioblastoma cells, opening new avenues for neurological disease therapies.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Neuroscience
Background:
- Effective siRNA delivery across the blood-brain barrier (BBB) is crucial for treating brain cancers like glioblastoma.
- Current delivery systems face challenges in crossing this biological barrier.
- Novel nanomedicines are needed to transport therapeutic oligonucleotides to the brain.
Purpose of the Study:
- To engineer bioreducible nanoparticles for systemic siRNA delivery to glioblastoma cells.
- To evaluate and optimize nanoparticle performance in crossing the BBB using a novel in vitro model.
- To demonstrate the therapeutic potential of these nanoparticles in an orthotopic mouse tumor model.
Main Methods:
- Development of bioreducible nanoparticles for siRNA encapsulation.
- Utilized a biomimetic in vitro model of the brain microvascular endothelium to assess BBB penetration.
- Transmission electron microscopy for visualizing nanoparticle transport mechanism.
- In vivo studies in an orthotopic mouse glioblastoma model for efficacy and safety assessment.
Main Results:
- Engineered nanoparticles successfully crossed the in vitro BBB model via a vesicular mechanism.
- Optimized nanoparticles demonstrated safe delivery across the BBB in vivo.
- Nanoparticles were internalized by human brain cancer cells, releasing siRNA into the cytosol.
- Achieved significant gene silencing both in vitro and in vivo in the tumor model.
Conclusions:
- The study presents a novel bioreducible nanocarrier for systemic siRNA delivery to the brain.
- The developed in vitro BBB model is effective for evaluating and engineering nanomedicines for brain delivery.
- This biodegradable nanocarrier shows promise for treating glioma and other neurological diseases through gene silencing.

