Immunoliposome-based targeted delivery of the CRISPR/Cas9gRNA-IL30 complex inhibits prostate cancer and prolongs survival

Abstract

The development of selective and nontoxic immunotherapy targeting prostate cancer (PC) is challenging. Interleukin (IL)30 plays immunoinhibitory and oncogenic roles in PC, and its tumor-specific suppression may have significant clinical implications. CRISPR/Cas9-mediated IL30 gene deletion in PC xenografts using anti-PSCA antibody-driven lipid nanocomplexes (Cas9gRNA-hIL30-PSCA NxPs) revealed significant genome editing efficiency and circulation stability without off-target effects or organ toxicity. Biweekly intravenous administration of Cas9gRNA-hIL30-PSCA NxPs to PC-bearing mice inhibited tumor growth and metastasis and improved survival. Mechanistically, Cas9gRNA-hIL30-PSCA NxPs suppressed ANGPTL 1/2/4, IL1β, CCL2, CXCL1/6, SERPINE1-F1, EFNB2, PLG, PF4, VEGFA, VEGFD, ANG, TGFβ1, EGF and HGF expression in human PC cells while upregulated CDH1, DKK3 and PTEN expression, leading to low proliferation and extensive ischemic necrosis. In the syngeneic PC model, IL30-targeting immunoliposomes downregulated NFKB1 expression and prevented intratumoral influx of CD11b+Gr-1+MDCs, Foxp3+Tregs, and NKp46+RORγt+ILC3, and prolonged host survival by inhibiting tumor progression. This study serves as a proof of principle that immunoliposome-based targeted delivery of Cas9gRNA-IL30 represent a potentially safe and effective strategy for PC treatment. Prostate cancer is an age-related disease and a leading cause of cancer death in men worldwide. Although its incidence has remained stable over the past decade, the proportion of tumors diagnosed in the advanced stages is rising, highlighting the need for improved and personalized treatments, especially for older patients with additional health problems. Di Carlo and coworkers created a NanoLiposome delivery system to transport a gene-editing tool, CRISPR/Cas9, directly to prostate cancer cells, to target and inhibit a particular gene involved in cancer growth. This study tested this approach’s effectiveness and safety on human prostate cancer cells and mouse models.　The findings show the potential of using NanoLiposomes for targeted gene editing in cancer. The researchers conclude that this method could provide a new and effective way to treat prostate cancer, particularly in patients requiring gentler treatment options. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.