One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting
Abstract Mutations in nuclear and mitochondrial genes are responsible for severe chronic disorders such as mitochondrial myopathies. Gene therapy using antisense oligonucleotides is a promising strategy to treat mitochondrial DNA (mtDNA) diseases by blocking the replication of the mutated mtDNA. How...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2023-12-01
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| Series: | Discover Nano |
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| Online Access: | https://doi.org/10.1186/s11671-023-03926-1 |
| _version_ | 1797376841450782720 |
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| author | Chloe Trayford Alissa Wilhalm Pamela Habibovic Hubert Smeets Florence van Tienen Sabine van Rijt |
| author_facet | Chloe Trayford Alissa Wilhalm Pamela Habibovic Hubert Smeets Florence van Tienen Sabine van Rijt |
| author_sort | Chloe Trayford |
| collection | DOAJ |
| description | Abstract Mutations in nuclear and mitochondrial genes are responsible for severe chronic disorders such as mitochondrial myopathies. Gene therapy using antisense oligonucleotides is a promising strategy to treat mitochondrial DNA (mtDNA) diseases by blocking the replication of the mutated mtDNA. However, transport vehicles are needed for intracellular, mitochondria-specific transport of oligonucleotides. Nanoparticle (NP) based vectors such as large pore mesoporous silica nanoparticles (LP) often rely on surface complexation of oligonucleotides exposing them to nucleases and limiting mitochondria targeting and controlled release ability. In this work, stable, fluorescent, hollow silica nanoparticles (HSN) that encapsulate and protect oligonucleotides in the hollow core were synthesized by a facile one-pot procedure. Both rhodamine B isothiocyanate and bis[3-(triethoxysilyl)propyl]tetrasulfide were incorporated in the HSN matrix by co-condensation to enable cell tracing, intracellular-specific degradation and controlled oligonucleotide release. We also synthesized LP as a benchmark to compare the oligonucleotide loading and release efficacy of our HSN. Mitochondria targeting was enabled by NP functionalization with cationic, lipophilic Triphenylphosphine (TPP) and, for the first time a fusogenic liposome based carrier, previously reported under the name MITO-Porter. HSN exhibited high oligonucleotide incorporation ratios and release dependent on intracellular degradation. Further, MITO-Porter capping of our NP enabled delayed, glutathione (GSH) responsive oligonucleotide release and mitochondria targeting at the same efficiency as TPP functionalized NP. Overall, our NP are promising vectors for anti-gene therapy of mtDNA disease as well as many other monogenic disorders worldwide. Graphical Abstract |
| first_indexed | 2024-03-08T19:44:25Z |
| format | Article |
| id | doaj.art-6b700379b3cc40748148803217c097a1 |
| institution | Directory Open Access Journal |
| issn | 2731-9229 |
| language | English |
| last_indexed | 2024-03-08T19:44:25Z |
| publishDate | 2023-12-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Nano |
| spelling | doaj.art-6b700379b3cc40748148803217c097a12023-12-24T12:26:58ZengSpringerDiscover Nano2731-92292023-12-0118111610.1186/s11671-023-03926-1One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targetingChloe Trayford0Alissa Wilhalm1Pamela Habibovic2Hubert Smeets3Florence van Tienen4Sabine van Rijt5Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht UniversityDepartment of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht UniversityDepartment of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht UniversityDepartment of Toxicogenomics, School for Mental Health and Neuroscience, Maastricht UniversityDepartment of Toxicogenomics, School for Mental Health and Neuroscience, Maastricht UniversityDepartment of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht UniversityAbstract Mutations in nuclear and mitochondrial genes are responsible for severe chronic disorders such as mitochondrial myopathies. Gene therapy using antisense oligonucleotides is a promising strategy to treat mitochondrial DNA (mtDNA) diseases by blocking the replication of the mutated mtDNA. However, transport vehicles are needed for intracellular, mitochondria-specific transport of oligonucleotides. Nanoparticle (NP) based vectors such as large pore mesoporous silica nanoparticles (LP) often rely on surface complexation of oligonucleotides exposing them to nucleases and limiting mitochondria targeting and controlled release ability. In this work, stable, fluorescent, hollow silica nanoparticles (HSN) that encapsulate and protect oligonucleotides in the hollow core were synthesized by a facile one-pot procedure. Both rhodamine B isothiocyanate and bis[3-(triethoxysilyl)propyl]tetrasulfide were incorporated in the HSN matrix by co-condensation to enable cell tracing, intracellular-specific degradation and controlled oligonucleotide release. We also synthesized LP as a benchmark to compare the oligonucleotide loading and release efficacy of our HSN. Mitochondria targeting was enabled by NP functionalization with cationic, lipophilic Triphenylphosphine (TPP) and, for the first time a fusogenic liposome based carrier, previously reported under the name MITO-Porter. HSN exhibited high oligonucleotide incorporation ratios and release dependent on intracellular degradation. Further, MITO-Porter capping of our NP enabled delayed, glutathione (GSH) responsive oligonucleotide release and mitochondria targeting at the same efficiency as TPP functionalized NP. Overall, our NP are promising vectors for anti-gene therapy of mtDNA disease as well as many other monogenic disorders worldwide. Graphical Abstracthttps://doi.org/10.1186/s11671-023-03926-1Intracellular degradationMitochondria targetingHollow silica nanoparticlesLarge pore silica nanoparticlesAnti-gene therapy |
| spellingShingle | Chloe Trayford Alissa Wilhalm Pamela Habibovic Hubert Smeets Florence van Tienen Sabine van Rijt One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting Discover Nano Intracellular degradation Mitochondria targeting Hollow silica nanoparticles Large pore silica nanoparticles Anti-gene therapy |
| title | One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting |
| title_full | One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting |
| title_fullStr | One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting |
| title_full_unstemmed | One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting |
| title_short | One-pot, degradable, silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting |
| title_sort | one pot degradable silica nanocarriers with encapsulated oligonucleotides for mitochondrial specific targeting |
| topic | Intracellular degradation Mitochondria targeting Hollow silica nanoparticles Large pore silica nanoparticles Anti-gene therapy |
| url | https://doi.org/10.1186/s11671-023-03926-1 |
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