Bioorthogonal Reaction-Mediated Tumor-Selective Delivery of CRISPR/Cas9 System for Dual-Targeted Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Immunology
• Genetics

Background:

• CRISPR-based cancer immunotherapy shows promise but faces delivery challenges.
• Efficient delivery of CRISPR systems to cancer cells is crucial for therapeutic efficacy.

Purpose of the Study:

• To develop a novel CRISPR/Cas9 tumor-targeting delivery strategy for enhanced dual-targeted cancer immunotherapy.
• To improve the efficacy of CRISPR-assisted immunotherapy by overcoming delivery limitations.

Main Methods:

• Utilized a tumor microenvironment (TME)-biodegradable hollow manganese dioxide (H-MnO2) nano-platform for in vivo metabolic labeling and cGAS-STING pathway activation.
• Employed in vivo click chemistry for targeted accumulation of CRISPR/Cas9 system-loaded liposomes within the tumor.
• Achieved gene editing to downregulate protein tyrosine phosphatase N2 (PTPN2) in tumor cells.

Main Results:

• Successfully achieved selective in vivo metabolic labeling and cGAS-STING pathway activation in tumors.
• Demonstrated targeted accumulation of CRISPR/Cas9 liposomes in modified tumor tissues.
• Showcased PTPN2 downregulation, leading to enhanced tumor sensitization to immunotherapy.
• Observed a potent antitumor response by boosting both innate and adaptive antitumor immunity.

Conclusions:

• The developed strategy offers a modular platform for precise in vivo gene editing.
• This approach effectively enhances dual-targeted cancer immunotherapy by improving CRISPR delivery and immune response.
• The findings highlight a promising new direction for overcoming delivery barriers in CRISPR-based cancer therapies.