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Updated: Oct 12, 2025
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
Published on: May 23, 2025
A programmable hierarchical-responsive nanoCRISPR elicits robust activation of endogenous target to treat cancer
Chao Liu1, Ning Wang1, Rui Luo1
1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University, Chengdu, 610041, P. R. China.
Abstract:
Despite promising progress of cancer gene therapy made, these therapeutics were still limited by the diversity of gene sizes and types. CRISPR/dCas9 mediated activation of tumor endogenous gene has shown great potential to surmount hinders of genetic varieties during the process of cancer gene therapy. However, the blood interference along with complicated tumor extra/intracellular microenvironment substantially compromise the performance of CRISPR/dCas9-based therapeutics in vivo. Methods: In this study, we constructed a programmable hierarchical-responsive nanoCRISPR (PICASSO) that can achieve sequential responses to the multiple physiological barriers in vivo. The core-shell structure endows PICASSO with long blood circulation capacity and tumor target accumulation as well as efficient cellular uptake and lysosomal escape, leading to high-performance of CRISPR/dCas9-mediated gene activation, which favors the antitumor efficacy. Results: Owing to these properties, PICASSO facilitated CRISPR/dCas9 mediated efficient transcriptional activation of various types of endogenous gene, and long non-protein-coding genes (LncRNA) containing targets ranging in size from ~1 kb to ~2000 kb in tumor cells. Intravenous administration of PICASSO to the tumor-bearing mice can achieve effective transcriptional activation of therapeutic endogenous gene, resulting in remarkable CRISPR/dCas9-mediate tumor inhibition with minimal adverse effect. Conclusions: Taken together, these characteristics allow PICASSO to unleash the potential of CRISPR/dCas9-based therapeutics in oncological treatment. The study provides a simple and versatile strategy to break through the restriction of sizes and types against cancer by utilization of tumor endogenous gene.
Insights
This study introduces PICASSO, a nanoCRISPR system that overcomes gene size and type limitations in cancer gene therapy. It effectively activates endogenous genes in tumors, showing promising antitumor efficacy with minimal side effects.
Area of Science:
- Biotechnology
- Molecular Biology
- Oncology
Background:
- Cancer gene therapy faces limitations due to diverse gene sizes and types.
- CRISPR/dCas9 activation of endogenous genes shows promise but is hindered by in vivo microenvironments.
- Existing CRISPR/dCas9 therapeutics struggle with delivery and efficacy in complex biological systems.
Purpose of the Study:
- To develop a novel CRISPR/dCas9 delivery system to overcome in vivo barriers for enhanced cancer gene therapy.
- To create a programmable, hierarchical-responsive nanoCRISPR (PICASSO) for efficient gene activation.
- To demonstrate the potential of PICASSO in activating diverse endogenous genes, including long non-protein-coding genes (LncRNA), for cancer treatment.
Main Methods:
- Constructed a programmable hierarchical-responsive nanoCRISPR (PICASSO) with a core-shell structure.
- PICASSO was designed for sequential responses to physiological barriers, ensuring long blood circulation, tumor targeting, cellular uptake, and lysosomal escape.
- Evaluated PICASSO's performance in CRISPR/dCas9-mediated gene activation and antitumor efficacy in tumor-bearing mice.
Main Results:
- PICASSO demonstrated efficient transcriptional activation of various endogenous genes, including LncRNA targets from ~1 kb to ~2000 kb in tumor cells.
- Intravenous administration of PICASSO in mice led to effective therapeutic gene activation.
- Remarkable CRISPR/dCas9-mediated tumor inhibition was observed with minimal adverse effects.
Conclusions:
- PICASSO effectively overcomes limitations in gene size and type for CRISPR/dCas9-based cancer gene therapy.
- The developed nanoCRISPR system enhances the potential of endogenous gene activation for oncological treatment.
- This strategy offers a versatile approach to advance cancer therapy by utilizing tumor endogenous genes.
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