Engineering Nanoparticles for Precision Gene Delivery into Brain

Speaker: Associate Professor Ruirui Qiao
Affiliate of Nanomaterials Centre
NHMRC Emerging Leadership Fellow
Australian Institute for Bioengineering and Nanotechnology

Engineering Nanoparticles for Precision Gene Delivery into Brain
 

The current clinical landscape of brain disease drug development includes up to 90% biotherapeutics (e.g., monoclonal antibodies and gene therapy) at phase III clinical trials.[1] However, their clinical translation of gene therapeutics is significantly hindered by poor penetration of the blood-brain barrier (BBB) (<1%) and low tissue and cell specificity.[2] Despite advancements in gene therapy, effective gene delivery to the brain remains a formidable challenge. The success of gene therapy for brain diseases can be achieved using engineered NPs that are safe, effective, and controllable. These NPs must protect nucleic acid cargo from degradation by circulatory nucleases, penetrate the BBB, efficiently target diseased cells, and escape the endosome to deliver the cargo effectively. To ensure efficient delivery, these engineered NPs must be optimally designed and carefully evaluated to address the complex challenges of gene delivery to the brain.

Since 2018, the Qiao group at AIBN, UQ has developed polymer-engineered magnetic nanoparticles using reversible addition–fragmentation chain-transfer polymerisation.[3] This approach enables precise and modular control over nanoparticle surface chemistry by integrating metal-chelating, biocompatible, stimuli-responsive, and functional moieties within a single polymer design. Using this platform, we have developed magnetic nanoparticles with highly bioinert surfaces that can circulate in the bloodstream with reduced immunogenicity compared with conventional PEG-based coatings.[4, 5]  More recently, we have expanded this platform toward nucleic acid delivery, developing multifunctional magnetic nanoparticle vectors for siRNA delivery across the BBB and tumour microenvironment-responsive gene silencing in medulloblastoma, the most common malignant brain tumour in children.[6]

In parallel, our group is developing droplet-engineered microgel platforms to create controlled, scalable, and physiologically relevant 3D cell microenvironments. These microgels can be engineered with tunable matrix composition, stiffness, size, and biochemical cues, providing modular building blocks for organoid culture, high-throughput disease modelling, and in vitro BBB model development. Such platforms offer an opportunity to evaluate nanoparticle transport, cell-specific uptake, therapeutic response, and toxicity in more human-relevant models before progressing to animal studies.

In this seminar, I will discuss how rational nanoparticle surface engineering and microgel-based tissue models can work together to address key barriers in brain delivery and brain disease research. I will focus on BBB penetration, disease-site targeting, intracellular siRNA release, and the development of engineered in vitro models to support the translation of next-generation precision delivery systems for neurological disease and brain cancer therapy.

References

1.             Gao, J.J., et al., Precision drug delivery to the central nervous system using engineered nanoparticles. Nature Reviews Materials, 2024.

2.             Mitchell, M.J., et al., Engineering precision nanoparticles for drug delivery. Nature Reviews Drug Discovery, 2021. 20(2): p. 101-124.

3.             Qiao, R., et al., Bioconjugation and Fluorescence Labeling of Iron Oxide Nanoparticles Grafted with Bromomaleimide-Terminal Polymers. Biomacromolecules, 2018. 19(11): p. 4423-4429.

4.             Li, Y., et al., Polymer-Assisted Magnetic Nanoparticle Assemblies for Biomedical Applications. ACS Applied Bio Materials, 2020. 3(1): p. 121-142.

5.             Qiao, R., et al., Sulfoxide-Containing Polymer-Coated Nanoparticles Demonstrate Minimal Protein Fouling and Improved Blood Circulation. Advanced Science, 2020. 7(13).

6.             Forgham, H., et al., Multifunctional Fluoropolymer-Engineered Magnetic Nanoparticles to Facilitate Blood-Brain Barrier Penetration and Effective Gene Silencing in Medulloblastoma. Advanced Science, 2024. 11(25).