<p>Milk-derived extracellular vesicles (mEVs), naturally occurring nanoparticles in bovine milk, have gained attention for their therapeutic potential and suitability as drug delivery systems. These vesicles exhibit unique properties, including biocompatibility, low immunogenicity, and stability in diverse biological environments, notably within the gastrointestinal tract, making them ideal for oral drug delivery. Studies have revealed their anti-inflammatory, antioxidant, and tissue-regenerative properties, as well as their ability to modulate gut microbiota. Recent advancements in engineering techniques have further enhanced the therapeutic applicability of mEVs, enabling effective drug loading and targeted delivery. Strategies such as surface modification, hybridization with synthetic nanoparticles, and various drug-loading methods have been employed to improve their stability, cargo capacity, and targeting efficiency. mEVs have shown promise in delivering nucleic acid-based therapies, addressing challenges like enzymatic degradation and poor bioavailability associated with oral administration. Preclinical studies demonstrate the ability of mEVs to traverse biological barriers, protect fragile therapeutics, and achieve functional gene modulation in target tissues. This focused review highlights the current understanding of the therapeutic properties of mEVs, engineering innovations, and their potential for oral administration of biological therapies. Despite considerable progress, challenges such as optimizing drug-loading efficiency, understanding long-term safety, and exploring mechanisms of intestinal uptake remain. Addressing these gaps will be critical for unlocking the full potential of mEVs as potentially cost-effective, scalable, safe and effective platforms for drug delivery in clinical settings.</p>