Systemic delivery of CRISPR-Cas9 nickase suppresses oncogene amplified cancer progression

ABSTRACT Oncogene amplification is a key driver of tumorigenesis and a perpetuator of genomic instability. Oncogene amplification accelerates cancer cell proliferation and evolution, contributing substantially to the enhancement of adaptation mechanisms, such as treatment resistance, which pose a significant therapeutic challenge. However, previous studies have shown oncogene amplification to be a critical vulnerability, rendering cancer cells, but not normal cells, susceptible to targeted, CRISPR-Cas9 nickase – mediated DNA damage and cell death in vitro. Here, we demonstrate the initial framework for the translation of this potential therapeutic approach utilizing Cas9D10A – mRNA and functionalized lipid nanoparticles for the targeted delivery, and suppression of disseminated MYCN-amplified neuroblastoma in vivo. Competing Interest Statement S.A.W. is a consultant for Editas Medicine and is on the scientific advisory board for Metagenomi Therapeutics. M.B.H. and S.A.W. have submitted a patent application to the US patent office pertaining to aspects of this work (application number PCT/US2025/019912).