Exosome-mediated post-transcriptional oncogene regulation as a novel cancer therapeutic strategy

Exosomes are tiny vesicles (30-150 nm in size) secreted by nearly every cell type that have lately emerged as essential regulators of intercellular communication and gene expression in cancer. They accommodate bioactive cargos such as miRNAs, lncRNAs, circRNAs, and mRNAs, all of which direct oncogene expression at the post-transcriptional level. Exosomal RNAs influence post-transcriptional and epigenetic regulatory mechanisms implicated in tumor activity, including mRNA degradation, translation repression and activation, alternative splicing interference, and epigenetic remodeling, which contribute to tumorigenic processes such as proliferation, angiogenesis, metastasis, immune evasion, and drug resistance. Tumor-derived exosomes also regulate the key oncogenic pathways such as PI3K/AKT, JAK/STAT, and Wnt/β-catenin to promote tumor stroma remodeling, thereby inducing macrophage M2 polarization, fibroblast transformation into cancer-associated fibroblasts, and pre-metastatic niche formation, favoring metastases. Targeting exosome-mediated oncogenic communication has therapeutic potential. Strategies include inhibiting exosome biogenesis and release using GW4869 or blocking Rab GTPases, blocking exosome uptake, and modulating oncogenic RNA cargo using antisense oligonucleotides, RNA interference, or CRISPR/Cas13-mediated RNA editing. Engineered exosomes also serve as natural, biocompatible carriers for the therapeutic delivery of siRNAs, miRNA mimics, mRNAs, or CRISPR components, offering improved stability, specificity, and reduced immunogenicity compared to synthetic counterparts. There are significant translational challenges, including large-scale manufacturing, purification, standardization, and biosafety testing, despite promising preclinical and early clinical results. In summary, comprehending and implementing post-transcriptional oncogene regulation via exosomes is a transformative strategy in precision oncology, creating new opportunities in targeted diagnosis, prognostication, and advanced cancer therapies.