Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells
Gene therapy approaches for mitochondrial DNA (mtDNA)-associated damage/diseases have thus far been limited, and despite advancements in single gene therapy for mtDNA mutations and progress in mitochondrial transplantation, no method exists for restoring the entire mtDNA molecule in a clinically tra...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000034 |
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| author | Kyrie Wilson Charles Holjencin Hwaran Lee Balasubramaniam Annamalai Masaaki Ishii Jeremy L. Gilbert Andrew Jakymiw Bärbel Rohrer |
| author_facet | Kyrie Wilson Charles Holjencin Hwaran Lee Balasubramaniam Annamalai Masaaki Ishii Jeremy L. Gilbert Andrew Jakymiw Bärbel Rohrer |
| author_sort | Kyrie Wilson |
| collection | DOAJ |
| description | Gene therapy approaches for mitochondrial DNA (mtDNA)-associated damage/diseases have thus far been limited, and despite advancements in single gene therapy for mtDNA mutations and progress in mitochondrial transplantation, no method exists for restoring the entire mtDNA molecule in a clinically translatable manner. Here, we present for the first time a strategy to deliver an exogenous, fully intact, and healthy mtDNA template into cells to correct endogenous mtDNA mutations and deletions, with the potential to be developed into an efficient pan-therapy for inherited and/or acquired mtDNA disorders. More specifically, the novel therapeutic nanoparticle complex used in our study was generated by combining a cell-penetrating peptide (CPP) with purified mtDNA, in conjunction with a mitochondrial targeting reagent. The generated nanoparticle complexes were found to be taken up by cells and localized to mitochondria, with exogenous mtDNA retention/maintenance, along with mitochondrial RNA and protein production, observed in mitochondria-depleted ARPE-19 cells at least 4 weeks following a single treatment. These data demonstrate the feasibility of restoring mtDNA in cells via a CPP carrier, with the therapeutic potential to correct mtDNA damage independent of the number of gene mutations found within the mtDNA. |
| format | Article |
| id | doaj-art-bf11fef5afea4b50b45b1430cb0bd547 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-bf11fef5afea4b50b45b1430cb0bd5472025-02-05T04:31:42ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102449Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cellsKyrie Wilson0Charles Holjencin1Hwaran Lee2Balasubramaniam Annamalai3Masaaki Ishii4Jeremy L. Gilbert5Andrew Jakymiw6Bärbel Rohrer7Department of Ophthalmology, College of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USADivision of Basic Science Research, Department of Biomedical & Community Health Sciences, James B. Edwards College of Dental Medicine, MUSC, Charleston, SC 29425, USADepartment of Bioengineering, Clemson University, Clemson – MUSC Bioengineering Program, MUSC, Charleston, SC 29425, USADepartment of Ophthalmology, College of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USADepartment of Ophthalmology, College of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USADepartment of Bioengineering, Clemson University, Clemson – MUSC Bioengineering Program, MUSC, Charleston, SC 29425, USADivision of Basic Science Research, Department of Biomedical & Community Health Sciences, James B. Edwards College of Dental Medicine, MUSC, Charleston, SC 29425, USA; Department of Biochemistry & Molecular Biology, College of Medicine, Hollings Cancer Center, MUSC, Charleston, SC 29425, USA; Corresponding author: Andrew Jakymiw, Division of Basic Science Research, Department of Biomedical & Community Health Sciences, James B. Edwards College of Dental Medicine, MUSC, Charleston, SC 29425, USA.Department of Ophthalmology, College of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA; Corresponding author: Bärbel Rohrer, Department of Ophthalmology, College of Medicine, Medical University of South Carolina (MUSC), Charleston, SC 29425, USA.Gene therapy approaches for mitochondrial DNA (mtDNA)-associated damage/diseases have thus far been limited, and despite advancements in single gene therapy for mtDNA mutations and progress in mitochondrial transplantation, no method exists for restoring the entire mtDNA molecule in a clinically translatable manner. Here, we present for the first time a strategy to deliver an exogenous, fully intact, and healthy mtDNA template into cells to correct endogenous mtDNA mutations and deletions, with the potential to be developed into an efficient pan-therapy for inherited and/or acquired mtDNA disorders. More specifically, the novel therapeutic nanoparticle complex used in our study was generated by combining a cell-penetrating peptide (CPP) with purified mtDNA, in conjunction with a mitochondrial targeting reagent. The generated nanoparticle complexes were found to be taken up by cells and localized to mitochondria, with exogenous mtDNA retention/maintenance, along with mitochondrial RNA and protein production, observed in mitochondria-depleted ARPE-19 cells at least 4 weeks following a single treatment. These data demonstrate the feasibility of restoring mtDNA in cells via a CPP carrier, with the therapeutic potential to correct mtDNA damage independent of the number of gene mutations found within the mtDNA.http://www.sciencedirect.com/science/article/pii/S2162253125000034MT: Delivery Strategiesmitochondriamitochondrial DNAmtDNAcell-penetrating peptidenucleic acid delivery |
| spellingShingle | Kyrie Wilson Charles Holjencin Hwaran Lee Balasubramaniam Annamalai Masaaki Ishii Jeremy L. Gilbert Andrew Jakymiw Bärbel Rohrer Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells Molecular Therapy: Nucleic Acids MT: Delivery Strategies mitochondria mitochondrial DNA mtDNA cell-penetrating peptide nucleic acid delivery |
| title | Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells |
| title_full | Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells |
| title_fullStr | Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells |
| title_full_unstemmed | Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells |
| title_short | Development of a cell-penetrating peptide-based nanocomplex for long-term delivery of intact mitochondrial DNA into epithelial cells |
| title_sort | development of a cell penetrating peptide based nanocomplex for long term delivery of intact mitochondrial dna into epithelial cells |
| topic | MT: Delivery Strategies mitochondria mitochondrial DNA mtDNA cell-penetrating peptide nucleic acid delivery |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000034 |
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