MicroRNA - Online First

MicroRNAs have emerged as pivotal post-transcriptional regulators, orchestrating a myriad of cellular processes critical to both normal physiology and pathological conditions, particularly cancer. Among these, miRNAs containing the highly conserved AAAGUGC seed sequence have garnered significant attention due to their multifaceted roles in cancer progression, acting as both oncogenes and tumour suppressors across a wide spectrum of malignancies. This review delves deeply into the evolutionary significance of AAAGUGC seed-containing miRNAs, elucidating their conserved nature and intricate roles in the regulation of cancer-related gene expression networks.

We focused on eight specific miRNAs- miR-17-5p, miR-20a-5p, miR-93-5p, miR-106a-5p, miR-106b-5p, miR-519d-3p, miR-526b-3p, and miR-20b-5p -each of which demonstrates context-dependent oncogenic or tumour-suppressive behaviour. Through an in-depth exploration of the molecular mechanisms by which these miRNAs modulate critical pathways, we highlighted their capacity to influence essential processes, including cell proliferation, apoptosis, epithelial-to-mesenchymal transition (EMT), metastasis, and drug resistance, reflecting the complexity of their regulatory roles.

Furthermore, we dissected the intricate interactions between these miRNAs and their downstream targets, showcasing their diverse contributions to the tumour microenvironment. The implications of miRNA dysregulation in chemotherapy resistance were also explored.

In conclusion, AAAGUGC seed-containing miRNAs represent a complex and evolutionarily conserved family with implications in cancer biology. Their ability to modulate multiple oncogenic and tumour-suppressive pathways highlights their potential as therapeutic targets or biomarkers in the context of personalized cancer treatment strategies. This review provides a comprehensive depth of current knowledge while proposing avenues for future research into the therapeutic manipulation of these miRNAs in combating cancer.

Colorectal Cancer (CRC) is the third most lethal cancer worldwide. Complex intercellular communication within the tumor microenvironment influences cancer progression, therapeutic resistance, with Exosomes (Exos) and Circulating Extracellular Vesicles (EVs) playing a critical role in this communication. Exosomes can impact recipient cells by carrying various biomolecules, promoting changes that support cancer progression. This review focuses specifically on exosome-derived noncoding RNAs (ncRNAs) in CRC, including microRNAs (miRNAs]), circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs), as significant regulators of cancer biology. The roles of these exosomal ncRNAs in CRC are central to tumor progression, metastasis, and treatment resistance. This review delves into specific molecular mechanisms, such as exosomal lncRNA H19, which enhances CRC chemoresistance by activating the β-catenin pathway, and exo-miR-21, which is implicated in 5-FU chemoresistance. We also highlight emerging evidence on exosomal circRNAs like circ_0006174, linked to doxorubicin resistance through miR-1205/CCND2 axis modulation. These exo-ncRNAs have shown promise as biomarkers and potential therapeutic targets, with studies indicating their diagnostic and prognostic capabilities in CRC patient cohorts. By examining recent in vivo and in vitro studies, we offer a comprehensive understanding of exosomal ncRNAs' roles in CRC pathogenesis and potential applications in clinical trials.

The revolutionary CRISPR/Cas9 gene editing technology holds immense potential for treating genetic diseases and tackling conditions like cancer. However, efficient delivery remains a significant challenge. This is where nanoparticles come into play, emerging as powerful allies in the realm of drug delivery. Nanoparticles can accommodate larger insertion sizes, enabling the incorporation of larger Cas9 enzymes and complex guide RNAs, thus opening up the possibility of editing previously inaccessible genetic regions. Their relatively straightforward and scalable production processes make them cost-effective options for wider applications. Notably, nanoparticles excel in vivo, demonstrating efficient tissue penetration and targeted delivery, which are crucial for maximizing therapeutic impact while minimizing side effects.

This review aims to explore the potential of nanoparticle-based delivery systems for CRISPR/Cas9, highlighting their advantages and challenges in gene editing applications. The diverse range of nanoparticles further bolsters their potential. Polymeric nanoparticles, for instance, offer tunable properties for customization and controlled release of the CRISPR cargo. Lipid-based nanoparticles facilitate efficient cellular uptake and endosomal escape, ensuring the CRISPR components reach the target DNA. Even gold nanoparticles, known for their unique biocompatibility and photothermal properties, hold promise in light-activated editing strategies. Non-viral delivery systems, particularly those based on nanoparticles, stand out due to their inherent advantages.

Collectively, the evidence paints a promising picture: nanoparticles are not merely passive carriers but active participants in the CRISPR/Cas9 delivery landscape. Their versatility, efficiency, and safety position them as key enablers of a future where gene editing can revolutionize drug development, offering personalized and targeted therapies for a wide range of diseases.