4.8 Article

CRISPR-dCas9-Guided and Telomerase-Responsive Nanosystem for Precise Anti-Cancer Drug Delivery

期刊

ACS APPLIED MATERIALS & INTERFACES
卷 13, 期 7, 页码 7890-7896

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acsami.0c19217

关键词

CRISPR-dCas9; telomerase; MSNs; drug delivery; nuclear targeting

资金

  1. National Key R&D Program of China [2019YFA0906000]
  2. Strategic Priority Research Program of Chinese Academy of Sciences [XDB29050201]
  3. National Natural Science Foundation of China [21705110, 81772737, 31925025, 91859108]
  4. National Major Science and Technology Projects [2018ZX10301405]
  5. Natural Science Foundation of Guangdong [2018B030306046]
  6. China Postdoctoral Science Foundation [2019M663154]
  7. Shenzhen Institute of Synthetic Biology Scientific Research Program [Y9G025]
  8. Shenzhen Municipal Government of China [JCYJ20170413161749433, JSGG20160301161836370]
  9. Sanming Project of Shenzhen Health and Family Planning Commission [SZSM201412018, SZSM201512037]
  10. High Level University's Medical Discipline Construction [2016031638]
  11. Shenzhen Health and Family Planning Commission [201606019]

向作者/读者索取更多资源

A CRISPR-dCas9-guided nanosystem was constructed for nuclear targeting and smart release of anticancer drugs, using telomerase-responsive technology to enhance efficiency. The nanosystem achieved precise drug delivery to the nucleus and triggered effective drug release in tumor cells. This study provides a promising strategy for nuclear-targeted delivery and tumor-specific release of anticancer drugs.
Nanodrug delivery systems are very promising for highly efficient anticancer drug delivery. However, the present nanosystems are commonly located in the cytoplasm and mediate uncontrolled release of drugs into cytosol, while a large number of anticancer drugs function more efficiently inside the nucleus. Here, we constructed a CRISPR-dCas9-guided and telomerase-responsive nanosystem for nuclear targeting and smart release of anticancer drugs. CRISPR-dCas9 technology has been employed to achieve conjugation of mesoporous silica nanoparticles (MSNs) with a high payload of the active anticancer drug, doxorubicin (DOX). A specifically designed wrapping DNA was used as a telomerase-responsive biogate to encapsulate DOX within MSNs. The wrapping DNA is extended in the presence of telomerase, which is highly activated in tumor cells, but not in normal cells. The extended DNA sequence forms a rigid hairpin-like structure and diffuses away from the MSN surface. CRISPR-dCas9 specifically targets telomere-repetitive sequences at the tips of chromosomes, facilitating the precise delivery of the nanosystem to the nucleus, and effective drug release triggered by telomerase that was enriched around telomeric repeats. This study provides a strategy and nanosystem for nuclear-targeted delivery and tumor-specific release of anticancer drugs that will maximize the efficiency of cancer cell destruction.

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