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In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super-Resolution Imaging and Genome Modification
Xiaoqian Ge1,2, Joseph B Wekselblatt3,4, Scott Elmore5
1Department of Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 26, 2025
Summary
Researchers discovered the N1 peptide, a novel tool for delivering biomolecules directly into neurons. This peptide bypasses the endocytic pathway, enabling efficient neurotherapeutics and advanced neuroscience research.
Area of Science:
- Neuroscience
- Biotechnology
- Molecular Biology
Background:
- Efficient delivery of biomolecules into neurons is crucial for central nervous system (CNS) therapeutics and neuroscience research.
- Current viral and non-viral methods often face limitations due to inefficient intracellular access via the endocytic pathway.
Purpose of the Study:
- To discover a novel neuron-targeting and direct cytosolic delivery platform for functional biomolecules.
- To overcome the limitations of existing delivery methods by bypassing the endocytic pathway.
Main Methods:
- A 15-amino-acid peptide, termed the N1 peptide, was identified and characterized.
- The N1 peptide's mechanism involves binding hyaluronan in the extracellular matrix and direct neuronal membrane passage.
- Delivery efficiency was assessed using fluorescent dyes for imaging and functional proteins like Cre recombinase for genome modification.
Main Results:
- The N1 peptide demonstrated neuron-specific targeting and direct cytosolic delivery of biomolecules.
- Efficient delivery of a fluorescent dye for super-resolution imaging of dendritic spines was achieved.
- Functional protein delivery, such as Cre recombinase, enabled site-specific genome modification.
- The N1 peptide showed robust neuronal specificity across diverse species (mice, rats, tree shrews, zebra finches).
- Effective targeting was confirmed via intraparenchymal, intrathecal, and intravenous injections post-blood-brain barrier opening with focused ultrasound (FUS).
Conclusions:
- The N1 peptide represents a versatile and functional platform for direct neuronal cytosolic delivery.
- This platform holds significant potential for advancing bioimaging and therapeutic applications in the CNS.
- The N1 peptide offers a promising alternative to overcome current biomolecule delivery challenges in neuroscience.
