The discovery of the link between microRNAs (miRNAs) and various human diseases, particularly cancer, has sparked significant interest in exploring miRNAs as a novel class of drugs. This has led to substantial investments in interdisciplinary research, including biology, chemistry, and medical science, for the development of miRNA-based therapies. The recent success of SARS-CoV-2 mRNA vaccines has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy, with advancements in RNA chemistry and delivery methods shaping the landscape of RNA-based immunotherapy. Despite substantial progress in preclinical research, miRNA-based therapeutics remain in their early stages, with only a few progressing to clinical development. None have reached phase III clinical trials or been approved by the US Food and Drug Administration (FDA). Several trials have faced termination due to toxicity issues, highlighting existing challenges that must be addressed for broad clinical application. Key challenges include establishing miRNA sensitivity, specificity, and selectivity, mitigating immunogenic reactions and off-target effects, developing enhanced targeted delivery methods, and determining optimal dosing while minimizing side effects. The therapeutic potential of miRNAs for various diseases is evident, but their precise functions and the technical and economic feasibility for widespread adoption are critical factors. A thorough risk evaluation is crucial to minimize off-target effects, prevent overdosing, and address various issues. Future investigations are essential to determine the applicability of miRNAs in clinical settings. miRNAs are short, non-coding RNA molecules that play pivotal roles in regulating gene expression at both transcriptional and post-transcriptional levels. They are involved in numerous biological processes and exhibit tissue-specific and developmental expression patterns. Dysregulation of miRNA function contributes to various diseases, including cancer, by upregulating or silencing specific target genes. MiRNA therapeutics aim to restore disrupted cellular functions by targeting and modulating the activity of specific endogenous miRNAs. Several miRNA-based therapeutics are currently in preclinical or clinical trials, targeting various diseases such as hepatitis C, Alport syndrome, fibrotic disorders, and immune disorders. However, challenges in precise delivery, immune evasion, and chemotherapy resistance persist. Small-molecule modulators of miRNA expression have also been explored to restore the function of tumor suppressor miRNAs or inhibit overexpressed oncogenic miRNAs. Advances in delivery methods, including lipid-based nanoparticles, polymeric vectors, and cell-derived membrane vesicles, aim to improve pharmacokinetics, tissue specificity, and reduce off-target effects. Despite these efforts, the field of miRNA-based therapeutics remains in its early stages, with significant challenges to be addressed before broad clinical application can be realized.The discovery of the link between microRNAs (miRNAs) and various human diseases, particularly cancer, has sparked significant interest in exploring miRNAs as a novel class of drugs. This has led to substantial investments in interdisciplinary research, including biology, chemistry, and medical science, for the development of miRNA-based therapies. The recent success of SARS-CoV-2 mRNA vaccines has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy, with advancements in RNA chemistry and delivery methods shaping the landscape of RNA-based immunotherapy. Despite substantial progress in preclinical research, miRNA-based therapeutics remain in their early stages, with only a few progressing to clinical development. None have reached phase III clinical trials or been approved by the US Food and Drug Administration (FDA). Several trials have faced termination due to toxicity issues, highlighting existing challenges that must be addressed for broad clinical application. Key challenges include establishing miRNA sensitivity, specificity, and selectivity, mitigating immunogenic reactions and off-target effects, developing enhanced targeted delivery methods, and determining optimal dosing while minimizing side effects. The therapeutic potential of miRNAs for various diseases is evident, but their precise functions and the technical and economic feasibility for widespread adoption are critical factors. A thorough risk evaluation is crucial to minimize off-target effects, prevent overdosing, and address various issues. Future investigations are essential to determine the applicability of miRNAs in clinical settings. miRNAs are short, non-coding RNA molecules that play pivotal roles in regulating gene expression at both transcriptional and post-transcriptional levels. They are involved in numerous biological processes and exhibit tissue-specific and developmental expression patterns. Dysregulation of miRNA function contributes to various diseases, including cancer, by upregulating or silencing specific target genes. MiRNA therapeutics aim to restore disrupted cellular functions by targeting and modulating the activity of specific endogenous miRNAs. Several miRNA-based therapeutics are currently in preclinical or clinical trials, targeting various diseases such as hepatitis C, Alport syndrome, fibrotic disorders, and immune disorders. However, challenges in precise delivery, immune evasion, and chemotherapy resistance persist. Small-molecule modulators of miRNA expression have also been explored to restore the function of tumor suppressor miRNAs or inhibit overexpressed oncogenic miRNAs. Advances in delivery methods, including lipid-based nanoparticles, polymeric vectors, and cell-derived membrane vesicles, aim to improve pharmacokinetics, tissue specificity, and reduce off-target effects. Despite these efforts, the field of miRNA-based therapeutics remains in its early stages, with significant challenges to be addressed before broad clinical application can be realized.