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Multistage Responsive NanoCRISPR Unleashes Cascade Amplified Endogenous Apoptosis and Inhibits Epithelial-Mesenchymal

Li Wang1, Chao Liu1,2, Jin Yang1

  • 1Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.

ACS Nano
|May 14, 2026
PubMed

Insights

A novel nanoCRISPR system effectively targets Survivin, a key protein in cancer resistance. This approach simultaneously induces apoptosis and inhibits metastasis for improved cancer therapy.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cancer Biology

Background:

  • Targeting apoptotic pathways is crucial for cancer treatment but faces challenges due to apoptosis resistance and metastasis.
  • Overexpression of Inhibitor of Apoptosis Proteins (IAPs), especially Survivin, significantly contributes to therapeutic resistance and cancer spread.
  • Existing single-pathway treatments are often insufficient to overcome these complex resistance mechanisms.

Purpose of the Study:

  • To develop a multistage-responsive nanoCRISPR (MIRV) system for targeting Survivin in both the nucleus and mitochondria.
  • To suppress tumor growth and metastasis by inducing apoptosis and inhibiting epithelial-mesenchymal transition (EMT).
  • To investigate the combined therapeutic effects of Survivin depletion and pro-apoptotic peptide delivery.

Main Methods:

  • Constructed a MIRV system with tumor-specific targeting, enzyme-triggered penetration, deshelling, and reactive oxygen species (ROS)-responsive capabilities.
  • Delivered Survivin-targeting CRISPR/Cas9 to the nucleus and the pro-apoptotic peptide D(KLAKLAK)2 to the cytoplasm of tumor cells.
  • Evaluated the system's efficacy in suppressing subcutaneous tumor growth and peritoneal metastasis in preclinical models.

Main Results:

  • The MIRV system successfully delivered its payload to target organelles within tumor cells.
  • Survivin depletion led to cascade-amplified endogenous apoptosis and inhibition of EMT.
  • Combined with peptide-induced mitochondrial dysfunction, MIRV significantly suppressed tumor growth and metastasis with minimal side effects.

Conclusions:

  • The MIRV system offers a potent strategy for simultaneously inducing apoptosis and suppressing EMT.
  • This dual-action approach demonstrates significant potential for effective antitumor and antimetastatic therapies.
  • MIRV represents a promising advancement in overcoming cancer resistance and improving therapeutic outcomes.
Keywords:
CRISPR/Cas9cascade-amplifiedendogenous apoptosisepithelial-mesenchymal transitionmultistage-responsive

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