Designing 4D printed drug delivery systems based on smart polymers and hydrogels: principles, strategies, and future perspectives

The development of advanced drug delivery systems (DDS) has revolutionized pharmaceutical applications by enabling precise, controlled, and targeted drug release.Polymer-based biodegradable systems have garnered notable attention within the field due to their inherent biocompatibility and the capacity to facilitate localized and sustained drug administration. Nonetheless, their widespread clinical adoption is hindered by challenges such as uncontrolled drug release kinetics, limited patient-specific customization, and scalability constraints. 3D printing overcomes these limitations by offering unparalleled design flexibility and customization, while 4D printing further addresses dynamic control challenges by enabling stimuli-responsive drug carriers for precise and targeted release. This review offers a comprehensive overview of 4D printing technologies for drug delivery applications, with a particular focus on a wide range of polymer-based smart materials. We discuss the basic principles of 3D printing, the evolution toward 4D printing, and the various stimuli-responsive mechanisms employed to achieve programmable drug release. We then explore key polymeric materials, including smart hydrogels, shape-memory polymers, self-healing polymers, and vitrimers, highlighting their potential in next-generation drug delivery platforms. Finally, we address the existing challenges and future perspectives of 4D printing in pharmaceutical applications, emphasizing the need for scalable, cost-effective, and clinically viable solutions.