Reinventing miRNA cancer therapy through immunomodulation and AI.

Despite the rational therapeutic premise of microRNA (miRNA) replacement or inhibition for cancer treatment, its clinical translation remains significantly constrained. Major challenges span from inherent molecular instability and off-target effects to substantial delivery hurdles. This persistent translational impasse continues despite continuous advancements in oligonucleotide chemistry and delivery platform engineering, underscoring an urgent need to re-evaluate the current developmental pathway. This review systematically delineates the significant therapeutic potential of miRNAs as pivotal gene regulators in oncology, alongside the current challenges in clinical translation posed by their unique biological complexity and delivery hurdles. Considering that, we highlight two pivotal frontiers poised to reshape the field: first, the strategic integration of miRNA therapeutics with modern immunotherapies to enhance anti-tumor efficacy; second, the application of artificial intelligence (AI) to deconvolute miRNA biology and accelerate rational drug design. An objective appraisal of persistent translational barriers, including robust in vivo target validation, long-term safety, and the interpretability of complex computational models, is also provided. We conclude that realizing the full clinical potential of miRNA therapy will necessitate a convergent approach, integrating intelligent delivery technologies, multi-omics-guided precision, and deep interdisciplinary collaboration.