Beyond structure: A review of intelligent, bioresponsive, and sustainable design paradigms for three-dimensional-printed metamaterials in drug delivery

Abstract

Drug administration involves the precise delivery of therapeutic agents to targeted sites in a controlled manner, maximizing efficacy while minimizing adverse effects. This goal is pursued through drug delivery systems (DDSs), built from synthetic, natural, or hybrid biomaterials, that encapsulate and release drugs via diverse administration routes and mechanisms. Their core purpose is to localize pharmacological activity, reduce systemic toxicity, and protect surrounding healthy tissues. Despite advances, persistent challenges remain, including poor bioavailability, instability in drug loading and release profiles, limited targeting accuracy, undesirable systemic persistence, and inadequate spatiotemporal control. Additional concerns include inadequate chemical stability, patient compliance, and risks of long-term toxicity, all of which hinder clinical translation. To overcome these obstacles, metamaterials—engineered structures with geometry-driven properties—have emerged as promising platforms. By leveraging additive manufacturing and nanoscale design, metamaterials offer tunable architectures and unconventional physicochemical properties, enabling precise control over release dynamics, spatial specificity, and therapeutic outcomes. This review highlights the integration of metamaterials into DDSs, focusing on material selection, structural design strategies, fabrication challenges, and the novel possibilities enabled by three-dimensional printing. We also examine their applications in sustained, pulsatile, and stimuli-responsive release, targeted therapy, theranostics, and regenerative medicine. Finally, we discuss unresolved issues such as biocompatibility, scalability, and translational barriers, emphasizing the transformative potential of metamaterial-enabled DDSs in advancing precision medicine and healthcare innovation.