Advanced intelligent drug-device combination systems: regulatory landscapes, technological foundations, and clinical...

Drug-device combinations (DDCs) have evolved from simple drug-coated implants into sophisticated intelligent platforms capable of real-time sensing, adaptive drug delivery, and closed-loop therapeutic control. This transformation is driven by converging advances in nanotechnology, biomaterials, controlled release mechanisms, wireless communication, artificial intelligence, and additive manufacturing. This review first systematically compares the divergent regulatory frameworks governing DDCs in the United States, European Union, and China. It then examines key enabling technologies and their integration into implantable, wearable, oral, and next-generation DDC platforms, emphasizing how functional convergence enables transition from passive delivery to feedback-controlled, patient-adaptive systems. Clinical applications are evaluated across therapeutic areas including ophthalmology, orthopedics, cardiovascular diseases, diabetes, oncology, and neurology, with attention to mechanistic distinctions and translational status. Finally, the review analyzes persistent technical, regulatory, and translational barriers. By connecting regulatory considerations, technological foundations, and clinical applications, this review offers a coherent roadmap for the next generation of intelligent DDCs.