Advances in MOF-Based Transdermal Drug Delivery Systems: Mechanisms, Applications, and Future Prospects.

Transdermal drug delivery offers a noninvasive alternative to conventional administration by avoiding gastrointestinal degradation and hepatic first-pass metabolism. However, its broader clinical application remains limited by the barrier function of the stratum corneum and insufficient drug accumulation within target tissues. Metal-organic frameworks (MOFs), characterized by their high surface area, tunable pore structures, and versatile surface chemistry, have recently emerged as promising platforms for transdermal drug delivery. This review summarizes the key advantages of MOF-based transdermal systems, including high drug-loading capacity, particularly for hydrophobic compounds and macromolecules, programmable multidrug delivery, favorable biocompatibility, and the integration of diagnostic and therapeutic functions with complementary physical treatment modalities. We further discuss recent advances in the rational design of MOF-based transdermal platforms across major biomedical applications, including diabetic wound management, skin regeneration, skin cancer therapy, and cosmetic delivery. Despite these advances, clinical translation remains challenged by insufficient long-term biosafety evaluation, incomplete understanding of degradation behavior and biodistribution, limited manufacturing scalability, and regulatory requirements for complex multifunctional systems. Recent developments in artificial intelligence (AI) provide new opportunities to address several of these challenges by accelerating MOF design, predicting structure-property relationships, optimizing stimuli-responsive drug release, and supporting the development of personalized transdermal therapies. Overall, this review provides an integrated perspective on the design principles, therapeutic applications, and translational challenges of MOF-based transdermal systems, while outlining future directions for their successful clinical development.