Stimuli-Responsive Zirconium-Based Metal-Organic Frameworks for Targeted Cancer Drug Delivery

Abstract

Metal-organic frameworks (MOFs) have emerged as versatile nanoplatforms for cancer drug delivery owing to their exceptionally high porosity, tunable pore architecture, modular composition, and flexible surface chemistry. In particular, zirconium-based MOFs (Zr-MOFs) have gained considerable attention owing to their good chemical stability, favorable biocompatibility, and ease of functional modification through coordination interactions. These attributes enable precise control over drug loading, surface functionalization, and stimulus-triggered release behavior. Recent advances in stimuli-responsive Zr-MOFs have enabled precise and tumor-selective drug delivery by utilizing intrinsic features of the tumor microenvironment (TME), such as acidic pH, redox gradients, elevated ATP levels, abnormal enzyme activity, and ionic variations, along with externally applied triggers, including light, heat, and ultrasound. This review presents a comprehensive and systematic overview of endogenous, exogenous, and multistimuli-responsive Zr-MOF nanoplatforms for targeted cancer drug delivery. We discuss key Zr-MOF structural families, design strategies for stimulus-responsive behavior, and the underlying structure-stimulus-function relationships that govern therapeutic performance. Representative examples are critically analyzed with respect to drug loading capacity, release mechanisms, targeting strategies, and in vitro and in vivo anticancer efficacy. Additionally, current limitations, including biosafety concerns, degradation behavior, tumor heterogeneity, and barriers to clinical translation, are addressed. Finally, future perspectives are outlined to support the rational development of next-generation Zr-MOF-based nanomedicines with improved precision, controllability, and clinical applicability.