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Regioselective Biolistic Targeting in Organotypic Brain Slices Using a Modified Gene Gun
Published on: October 24, 2014
Programming Brain Cell-Type-Selective Delivery In Vivo with Transporter-Guided Therapeutics
Roshan W Gunasekara1, Lejie Zhang1, Lei Tong1
1Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA.
Biorxiv : the Preprint Server for Biology
|June 29, 2026
Summary
Researchers developed a novel platform for targeted drug delivery, ExACT (Exogenous Cellular Targeting), enabling precise intracellular delivery to specific cell types by leveraging natural cell transporters. This breakthrough promises enhanced therapeutic efficacy and reduced side effects for various diseases.
Area of Science:
- Pharmacology
- Cell Biology
- Neuroscience
Background:
- Many diseases stem from specific cell population dysfunction.
- Current therapeutics often lack cell-type specificity, leading to limited efficacy and increased toxicity.
- Targeted intracellular delivery remains a significant challenge in pharmacotherapy.
Purpose of the Study:
- To develop a platform for cell-type-selective intracellular drug delivery.
- To identify and utilize endogenous membrane transporters for targeted uptake.
- To demonstrate the potential of this platform for precision pharmacotherapy.
Main Methods:
- Developed the ExACT (Exogenous Cellular Targeting) platform for cell-type-selective intracellular delivery.
- Conducted in vivo screening of small-molecule libraries in mouse brains to identify transporter-mediated uptake.
- Utilized humanized mouse models and human iPSC-derived cells to validate transporter selectivity.
- Engineered neurons with ectopic transporter expression to create synthetic entry ports.
- Created bifunctional conjugates linking transporter-targeting motifs to therapeutic payloads (ASOs, small molecules).
Main Results:
- Identified small molecules with preferential uptake in neurons, astrocytes, pericytes, and endothelial cells based on endogenous transporter expression.
- Discovered a series of compounds with high selectivity for brain and retinal endothelium mediated by Slco1a4.
- Demonstrated conserved selectivity of the human orthologue SLCO1A2 in humanized mouse models and human oligodendrocytes.
- Showcased successful targeted delivery to gene-therapy-modified neurons expressing SLCO1A2.
- Confirmed retention of pharmacological activity in bifunctional conjugates, achieving transporter-dependent cell-type selectivity.
Conclusions:
- The ExACT platform effectively achieves cell-type-selective intracellular delivery by exploiting membrane transporters.
- Transporter diversity can be harnessed for precision pharmacotherapy, enabling targeted drug delivery to specific cell populations.
- This approach holds significant potential for developing more effective and safer therapeutics with reduced off-target effects.
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