RNA‐Based and Gene Therapy Approaches in Cancer Treatment

Cancer remains a leading cause of mortality worldwide, but rapid advances in RNA-based and gene-editing therapies are reshaping therapeutic strategies beyond conventional chemotherapy. This chapter reviews how small RNAs, particularly microRNAs (miRNAs) and small interfering RNAs (siRNAs), and programmable nucleases such as CRISPR–Cas systems, TALENs, and ZFNs are being used for precision cancer therapy. The chapter outlines the principles of miRNA biology and then discusses miRNA mimics and anti-miRNA oligonucleotides (AMOs), miRNA sponges, and small-molecule inhibitors that restore tumor suppressor miRNAs or inhibit oncomiRs. Key clinical candidates discussed in the chapter illustrate both the promise and immunotoxicity hurdles of miRNA therapeutics. The chapter further summarizes the expanding siRNA pipeline, highlighting allele-selective agents such as siG12D-LODER and emerging candidates like NUDT21 and TGF-β/COX-2 targeting siRNAs that exemplify rational targeting of oncogenic drivers and the tumor microenvironment. We describe the evolution from ZFNs and TALENs to CRISPR-based platforms and their application in cancer, including functional genomic screens, rapid in vivo tumor modeling, and the engineering of next-generation CAR-T and TCR-T cells. Case studies such as TALEN-edited allogeneic CAR-T products (e.g., UCART/ALLO series) and multiplex CRISPR-edited CD19 or BCMA CAR-T therapies demonstrate the feasibility, early efficacy, and scalability of genome-edited cell therapies. The chapter also highlights CRISPR strategies that directly target oncogenes, reverse drug resistance pathways, or repair tumor suppressor networks. Finally, we discuss major translational barriers to nucleic acid delivery to solid tumors, off-target effects, p53-associated genotoxicity, and innate immune activation and survey emerging solutions such as optimized nanoparticles for delivery approaches. Looking ahead, integration of multi-omics profiling with rapidly reprogrammable RNA and genome editors may enable iterative, patient-specific interventions that continuously anticipate and overcome tumor evolution