Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids
Therapeutic nucleic acids (TNAs) including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) have emerged as promising treatment strategies for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic n...
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MDPI AG
2024-12-01
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| author | Randall Allen Toshifumi Yokota |
| author_facet | Randall Allen Toshifumi Yokota |
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| description | Therapeutic nucleic acids (TNAs) including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) have emerged as promising treatment strategies for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic nucleic acid-like molecules provide unique advantages over traditional pharmacological agents, including the ability to target previously “undruggable” genes. Despite this promise, several biological barriers severely limit their clinical efficacy. Upon administration, TNAs primarily enter cells through endocytosis, becoming trapped inside membrane-bound vesicles known as endosomes. Studies estimate that only 1–2% of TNAs successfully escape endosomal compartments to reach the cytosol, and in some cases the nucleus, where they bind target mRNA and exert their therapeutic effect. Endosomal entrapment and inefficient nuclear localization are therefore critical bottlenecks in the therapeutic application of TNAs. This review explores the current understanding of TNA endosomal escape and nuclear transport along with strategies aimed at overcoming these challenges, including the use of endosomal escape agents, peptide-TNA conjugates, non-viral delivery vehicles, and nuclear localization signals. By improving both endosomal escape and nuclear localization, significant advances in TNA-based therapeutics can be realized, ultimately expanding their clinical utility. |
| format | Article |
| id | doaj-art-4f5cee9107954c27822350a7f00b190b |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj-art-4f5cee9107954c27822350a7f00b190b2025-08-20T02:43:49ZengMDPI AGMolecules1420-30492024-12-012924599710.3390/molecules29245997Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic AcidsRandall Allen0Toshifumi Yokota1Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaDepartment of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, CanadaTherapeutic nucleic acids (TNAs) including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) have emerged as promising treatment strategies for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic nucleic acid-like molecules provide unique advantages over traditional pharmacological agents, including the ability to target previously “undruggable” genes. Despite this promise, several biological barriers severely limit their clinical efficacy. Upon administration, TNAs primarily enter cells through endocytosis, becoming trapped inside membrane-bound vesicles known as endosomes. Studies estimate that only 1–2% of TNAs successfully escape endosomal compartments to reach the cytosol, and in some cases the nucleus, where they bind target mRNA and exert their therapeutic effect. Endosomal entrapment and inefficient nuclear localization are therefore critical bottlenecks in the therapeutic application of TNAs. This review explores the current understanding of TNA endosomal escape and nuclear transport along with strategies aimed at overcoming these challenges, including the use of endosomal escape agents, peptide-TNA conjugates, non-viral delivery vehicles, and nuclear localization signals. By improving both endosomal escape and nuclear localization, significant advances in TNA-based therapeutics can be realized, ultimately expanding their clinical utility.https://www.mdpi.com/1420-3049/29/24/5997therapeutic nucleic acidsantisense oligonucleotidessmall interfering RNAendosomal escapenuclear localizationdrug delivery |
| spellingShingle | Randall Allen Toshifumi Yokota Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids Molecules therapeutic nucleic acids antisense oligonucleotides small interfering RNA endosomal escape nuclear localization drug delivery |
| title | Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids |
| title_full | Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids |
| title_fullStr | Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids |
| title_full_unstemmed | Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids |
| title_short | Endosomal Escape and Nuclear Localization: Critical Barriers for Therapeutic Nucleic Acids |
| title_sort | endosomal escape and nuclear localization critical barriers for therapeutic nucleic acids |
| topic | therapeutic nucleic acids antisense oligonucleotides small interfering RNA endosomal escape nuclear localization drug delivery |
| url | https://www.mdpi.com/1420-3049/29/24/5997 |
| work_keys_str_mv | AT randallallen endosomalescapeandnuclearlocalizationcriticalbarriersfortherapeuticnucleicacids AT toshifumiyokota endosomalescapeandnuclearlocalizationcriticalbarriersfortherapeuticnucleicacids |