Mesenchymal stem cells (MSCs) are known for their ability to differentiate and self-renew, playing a critical role in tissue homeostasis and repair. Despite their therapeutic potential, clinical applications of MSCs face challenges, including safety concerns and uncertain effects on tumors. In contrast, MSC-derived exosomes (MSC-EXOs) have shown comparable or superior efficacy across various diseases, primarily due to their cargo of functional RNAs and proteins. These natural nanovesicles offer a promising drug delivery platform, combining the advantages of both MSCs and exosomes. Genetic engineering approaches, such as surface modification and drug loading, further enhance their therapeutic capabilities. Small RNA drugs present novel opportunities for expanding therapeutic targets, but efficient delivery remains a significant challenge. MSC-EXOs, either natural or engineered, provide a safe and effective solution for delivering small RNA drugs, holding great promise for both research and translational applications. However, large-scale production of MSC-EXOs remains a key hurdle, and ongoing efforts focus on optimizing strategies for producing high-quality MSC-EXOs in sufficient quantities for industrial and clinical use. This review examines the role of MSC-EXOs in small RNA drug delivery, highlighting the associated challenges and potential solutions for scalable production.