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Abstract

Precision oncology targets cancer cells using antibodies or small-molecule inhibitors directed against a mutated or overexpressed oncogenic protein. Targeted drugs are developed individually for each protein at huge costs, and only a small fraction of proteins can be targeted at all. We propose to target cancer cells through their mutated transcripts and genomes instead, leveraging their mutations to alert the immune system. Nanoparticles delivered systemically could be loaded with RNA- or DNA-directed Cas mRNA and guide RNAs targeting multiple patient-specific cancer mutations. In transcriptome-targeted immunotherapy, patient-specific guide RNAs would target CRISPR/Cas to cleave the transcripts mutated in the patient's cancer cells. The cleaved transcripts would hybridize with patient-specific 5'-triphosphate RNAs to form blunt-ended dsRNAs, triggering RIG-I and type-I interferon signaling that induces a strong systemic, long-lasting immune response against all cancer cells. This approach could potentially work for all cancers and prevent resistance by targeting many mutations jointly.