In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome Modification
Abstract Efficient delivery of biomolecules into neurons has significant impacts on therapeutic applications in the central nervous system (CNS) and fundamental neuroscience research. Existing viral and non‐viral delivery methods often suffer from inefficient intracellular access due to the endocyti...
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| Format: | Article |
| Language: | English |
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202501033 |
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| author | Xiaoqian Ge Joseph B. Wekselblatt Scott Elmore Bo Wang Tongtong Wang Renjinming Dai Tingting Zhang Harsh Dave Mohammadaref Ghaderi Athul Raj Anilkumar Bill Wang Shashank R. Sirsi Jung‐Mo Ahn Mikhail G. Shapiro Yuki Oka Carlos Lois Zhenpeng Qin |
| author_facet | Xiaoqian Ge Joseph B. Wekselblatt Scott Elmore Bo Wang Tongtong Wang Renjinming Dai Tingting Zhang Harsh Dave Mohammadaref Ghaderi Athul Raj Anilkumar Bill Wang Shashank R. Sirsi Jung‐Mo Ahn Mikhail G. Shapiro Yuki Oka Carlos Lois Zhenpeng Qin |
| author_sort | Xiaoqian Ge |
| collection | DOAJ |
| description | Abstract Efficient delivery of biomolecules into neurons has significant impacts on therapeutic applications in the central nervous system (CNS) and fundamental neuroscience research. Existing viral and non‐viral delivery methods often suffer from inefficient intracellular access due to the endocytic pathway. Here, a neuron‐targeting and direct cytosolic delivery platform is discovered by using a 15‐amino‐acid peptide, termed the N1 peptide, which enables neuron‐specific targeting and cytosolic delivery of functional biomolecules. The N1 peptide initially binds hyaluronan in the extracellular matrix and subsequently passes the membrane of neurons without being trapped into endosome. This mechanism facilitates the efficient delivery of cell‐impermeable and photo‐stable fluorescent dye for super‐resolution imaging of dendritic spines, and functional proteins, such as Cre recombinase, for site‐specific genome modification. Importantly, the N1 peptide exhibits robust neuronal specificity across diverse species, including mice, rats, tree shrews, and zebra finches. Its targeting capability is further demonstrated through various administration routes, including intraparenchymal, intrathecal, and intravenous (i.v.) injections after blood‐brain barrier (BBB) opening with focused ultrasound (FUS). These findings establish the N1 peptide as a versatile and functional platform with significant potential for bioimaging and advanced therapeutic applications. |
| format | Article |
| id | doaj-art-469bd6083db24ddeae52e5340d7a4580 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-469bd6083db24ddeae52e5340d7a45802025-08-20T03:15:35ZengWileyAdvanced Science2198-38442025-07-011225n/an/a10.1002/advs.202501033In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome ModificationXiaoqian Ge0Joseph B. Wekselblatt1Scott Elmore2Bo Wang3Tongtong Wang4Renjinming Dai5Tingting Zhang6Harsh Dave7Mohammadaref Ghaderi8Athul Raj Anilkumar9Bill Wang10Shashank R. Sirsi11Jung‐Mo Ahn12Mikhail G. Shapiro13Yuki Oka14Carlos Lois15Zhenpeng Qin16Department of Biomedical Engineering University of Texas Southwestern Medical Center Dallas TX 75390 USADivision of Chemistry and Chemical Engineering California Institute of Technology Pasadena CA 91125 USADepartment of Chemistry and Biochemistry University of Texas at Dallas Richardson TX 75080‐3021 USADivision of Biology and Biological Engineering California Institute of Technology Pasadena CA 91125 USADivision of Biology and Biological Engineering California Institute of Technology Pasadena CA 91125 USADepartment of Bioengineering University of Texas at Dallas Richardson TX 75080‐3021 USADepartment of Mechanical Engineering University of Texas at Dallas Richardson TX 75080‐3021 USADepartment of Bioengineering University of Texas at Dallas Richardson TX 75080‐3021 USADepartment of Bioengineering University of Texas at Dallas Richardson TX 75080‐3021 USADepartment of Bioengineering University of Texas at Dallas Richardson TX 75080‐3021 USADepartment of Bioengineering University of Texas at Dallas Richardson TX 75080‐3021 USADepartment of Bioengineering University of Texas at Dallas Richardson TX 75080‐3021 USADepartment of Chemistry and Biochemistry University of Texas at Dallas Richardson TX 75080‐3021 USADivision of Chemistry and Chemical Engineering California Institute of Technology Pasadena CA 91125 USADivision of Biology and Biological Engineering California Institute of Technology Pasadena CA 91125 USADivision of Biology and Biological Engineering California Institute of Technology Pasadena CA 91125 USADepartment of Biomedical Engineering University of Texas Southwestern Medical Center Dallas TX 75390 USAAbstract Efficient delivery of biomolecules into neurons has significant impacts on therapeutic applications in the central nervous system (CNS) and fundamental neuroscience research. Existing viral and non‐viral delivery methods often suffer from inefficient intracellular access due to the endocytic pathway. Here, a neuron‐targeting and direct cytosolic delivery platform is discovered by using a 15‐amino‐acid peptide, termed the N1 peptide, which enables neuron‐specific targeting and cytosolic delivery of functional biomolecules. The N1 peptide initially binds hyaluronan in the extracellular matrix and subsequently passes the membrane of neurons without being trapped into endosome. This mechanism facilitates the efficient delivery of cell‐impermeable and photo‐stable fluorescent dye for super‐resolution imaging of dendritic spines, and functional proteins, such as Cre recombinase, for site‐specific genome modification. Importantly, the N1 peptide exhibits robust neuronal specificity across diverse species, including mice, rats, tree shrews, and zebra finches. Its targeting capability is further demonstrated through various administration routes, including intraparenchymal, intrathecal, and intravenous (i.v.) injections after blood‐brain barrier (BBB) opening with focused ultrasound (FUS). These findings establish the N1 peptide as a versatile and functional platform with significant potential for bioimaging and advanced therapeutic applications.https://doi.org/10.1002/advs.202501033across speciesgenome modificationneuron specific targetingpeptidessuper‐resolution imaging |
| spellingShingle | Xiaoqian Ge Joseph B. Wekselblatt Scott Elmore Bo Wang Tongtong Wang Renjinming Dai Tingting Zhang Harsh Dave Mohammadaref Ghaderi Athul Raj Anilkumar Bill Wang Shashank R. Sirsi Jung‐Mo Ahn Mikhail G. Shapiro Yuki Oka Carlos Lois Zhenpeng Qin In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome Modification Advanced Science across species genome modification neuron specific targeting peptides super‐resolution imaging |
| title | In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome Modification |
| title_full | In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome Modification |
| title_fullStr | In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome Modification |
| title_full_unstemmed | In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome Modification |
| title_short | In Vivo Cytosolic Delivery of Biomolecules into Neurons for Super‐Resolution Imaging and Genome Modification |
| title_sort | in vivo cytosolic delivery of biomolecules into neurons for super resolution imaging and genome modification |
| topic | across species genome modification neuron specific targeting peptides super‐resolution imaging |
| url | https://doi.org/10.1002/advs.202501033 |
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