Title : In vivo delivery of CRISPR Cas9 using lipid nanoparticles enables gene depletion to enhance immunotherapy in cancer
Abstract:
Cancer acquires and metabolizes nutrients through aerobic glycolysis, synthesizing macromolecular precursors to support cancer cell survival. Therefore, targeting cancer metabolic oncoproteins represents a new concept in the development of effective cancer therapeutics. PFKP, also known as platelet phosphofructokinase, is an enzyme that plays a critical role in cellular metabolism. It is involved in the regulation of glycolysis, the metabolic pathway that converts glucose into energy. Our previous study demonstrated elevated expression of PFKP in head and neck squamous cell carcinoma (HNSCC) primary tissues and cultured cell lines. Loss of function suppresses HNSCC cell growth and induces tumor regression in orthotopic tumor-bearing mice. Several inhibitors targeting glycolytic enzymes, including PFKP, are being investigated in preclinical and clinical trials as potential anticancer agents, but the overall response rate remains low. CRISPR-Cas9 has revolutionized genome engineering and has been widely used to modify cancer-associated genes. However, challenges remain as CRISPR editing components must be transported into cells to exert their function. There is a need to explore effective in vivo delivery systems to accelerate the clinical application of CRISPR-Cas9. We recently developed CRISPR-based PFKP-targeting nanodrugs by loading Cas9 mRNA and anti-PFKP sgRNAs into lipid nanoparticles (LNPs), which have become a clinically acceptable delivery system due to their low toxicity and high delivery efficacy and biocompatibility. As expected, LNP-sgPFKP treatment of tongue tumors established in immunocompetent C57BJ/6 mice remarkably suppressed tumor growth. Most interestingly, LNP-sgPFKP acted synergistically with anti-PD1 antibody and significantly primed CD8+ T cells, resulting in durable anticancer activity against HNSCC compared to monotherapy. These novel and significant findings demonstrate a novel approach to inhibit PFKP in tumor cells and provide a potential therapeutic strategy to enhance the success of multimodality therapy in cancer patients.
Audience Take Away Notes:
- We will present recent advances in the field of nanoparticle-mediated targeted therapeutics for head and neck cancer, with a focus on target sites
- We will also demonstrate the tremendous potential of nanoparticle-based targeted therapeutics to address the need for viable alternative cancer therapies and encourage the audience to further explore more specific tumor targets and more efficient nanocarriers
