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Therapeutic genome editing of triple-negative breast tumors using a noncationic and deformable nanolipogel

Peng Guo1,2,3, Jiang Yang1,2,3, Jing Huang1,2,3

  • 1Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|August 28, 2019
PubMed

Insights

A novel nanolipogel system (tNLG) effectively delivers CRISPR genome editing to triple-negative breast cancer (TNBC) tumors. This approach targets the Lcn2 oncogene, significantly inhibiting TNBC cell migration and tumor growth.

Area of Science:

  • Biomedical Engineering
  • Oncology
  • Gene Therapy

Background:

  • Triple-negative breast cancer (TNBC) presents a high mortality rate and lacks effective therapeutics.
  • CRISPR genome editing offers therapeutic potential for TNBC, but safe and effective in vivo delivery remains a challenge.
  • Nonviral delivery systems are crucial for clinical translation of CRISPR-based therapies.

Purpose of the Study:

  • To develop and evaluate a novel noncationic, deformable, and tumor-targeted nanolipogel system (tNLG) for CRISPR genome editing in TNBC.
  • To assess the efficacy of tNLGs in delivering CRISPR to knockout the Lcn2 oncogene in TNBC cells.
  • To determine the therapeutic impact of Lcn2 inhibition on TNBC progression and tumor growth in vivo.

Main Methods:

  • Synthesis and characterization of the tumor-targeted nanolipogel (tNLG) system.
  • In vitro and in vivo CRISPR-Cas9 genome editing targeting Lipocalin 2 (Lcn2) in human TNBC cells.
  • Evaluation of Lcn2 knockout effects on TNBC cell migration and mesenchymal phenotype.
  • Assessment of tNLG delivery, Lcn2 knockout efficiency, and tumor growth suppression in an orthotopic TNBC mouse model.

Main Results:

  • The tNLG system was successfully synthesized and demonstrated deformability and tumor-targeting capabilities.
  • tNLGs mediated potent CRISPR knockout of Lcn2 in TNBC cells both in vitro and in vivo.
  • Loss of Lcn2 significantly inhibited TNBC cell migration and mesenchymal characteristics.
  • Systemic administration of tNLGs achieved >81% Lcn2 knockout in TNBC tumors, leading to >77% tumor growth suppression.

Conclusions:

  • The developed tNLG system serves as a safe, precise, and effective nonviral delivery vehicle for CRISPR genome editing in TNBC.
  • Targeting the Lcn2 oncogene via CRISPR/tNLG delivery attenuates TNBC aggressiveness and suppresses tumor growth.
  • This study provides a promising proof-of-concept for tNLG-mediated in vivo gene editing as a therapeutic strategy for TNBC.
Keywords:
CRISPR genome editingICAM1nanolipogeltriple-negative breast cancer

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