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Overcoming Pharmaceutical Bottlenecks for Nucleic Acid Drug Development.
Lu, Mei; Xing, Haonan; Zheng, Aiping; Huang, Yuanyu; Liang, Xing-Jie.
  • Lu M; Advanced Research Institute of Multidisciplinary Science, School of Life Science, School of Medical Technology, Key Laboratory of Molecular Medicine and Biotherapy, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, No. 5, South Street, Zhonggu
  • Xing H; Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing 100190, China.
  • Zheng A; Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing 100190, China.
  • Huang Y; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, No. 27, Taiping Road, Beijing 100850, China.
  • Liang XJ; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, No. 27, Taiping Road, Beijing 100850, China.
Acc Chem Res ; 56(3): 224-236, 2023 02 07.
Article in English | MEDLINE | ID: covidwho-2185418
ABSTRACT
The outbreak of the coronavirus disease 2019 (COVID-19) pandemic and swift approval of two mRNA vaccines have put nucleic acid therapeutics in the spotlight of both the scientific community and the general public. Actually, in addition to mRNAs, multiple nucleic acid therapeutics have been successively commercialized over the past few years. The rapid development of nucleic acid drugs not only demonstrates their superior potency but also marks a new era of the field. Compared with conventional treatments targeting proteins rather than the root causes of diseases at the genetic level, nucleic acids are capable of achieving long-standing or even curative effects against undruggable disorders by modulating gene expression via inhibition, editing, addition, or replacement. This offers a terrific arsenal for expanding therapeutic access to diseases lacking current treatment options and developing vaccines to provide swift responses to emerging global health threats.Despite the stunning success and recent resurgence of interest in the field, the unfavorable physicochemical characteristics (i.e., the negative charge, large molecular weight, and hydrophilicity), susceptibility to nuclease degradation, off-target toxicity, and immunogenicity are a brake for moving nucleic acid therapeutics from bench to bedside. Currently, developing technologies to improve the circulation stability, targeting affinity, cellular entry, endolysosomal escape, efficacy, and safety of nucleic acid drugs still remains a major pharmaceutical bottleneck.In this Account, we outline the research efforts from our group on the development of technology platforms to overcome the pharmaceutical bottlenecks for nucleic acid therapeutics. We have engineered a variety of intelligent delivery platforms such as synthetic nanomaterials (i.e., lipid nanoparticles, polymers, and inorganic nanoparticles), physical delivery methods (i.e., electroporation), and naturally derived vehicles (i.e., extracellular vesicles), aiming at endowing nucleic acids with improved circulation stability, targeting affinity, and cellular internalization (Get in) and stimuli responsive endolysosomal escape capability (Get out). Moreover, we will discuss our progress in developing a series of modification strategies for sequence engineering of nucleic acids to endow them with enhanced nuclease resistance, translation efficiency, and potency while alleviating their off-target toxicity and immunogenicity (Sequence engineering). Integrating these technologies may promote the development of nucleic acid therapeutics with potent efficacy and improved safety (Efficacy & safety). With this Account, we hope to offer insights into rational design of cutting-edge nucleic acid therapeutic platforms. We believe that the continuing advances in nucleic acid technologies together with academic-industry collaborations in the clinic, will promise to usher in more clinically translatable nucleic acid therapeutics in the foreseeable future.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Nanostructures / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: Acc Chem Res Year: 2023 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Nanostructures / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Humans Language: English Journal: Acc Chem Res Year: 2023 Document Type: Article