Precision Design of Defect-Engineered MOFs: From Synthetic Strategies to Biomedical Applications

Comprehensive Summary: Metal–organic frameworks (MOFs) have shown great potential as highly ordered porous materials in biomedical applications. However, the perfect crystalline structure of conventional MOFs often leads to limitations such as rigid active sites, restricted mass transport, and insufficient loading capacity. Defect engineering, through the intentional introduction of structural defects (such as missing-linker and missing-cluster), has emerged as an important strategy to overcome these constraints. It can significantly expand pore volumes, enhance surface accessibility, and endow the materials with enzyme-mimicking activities. Despite the rapid development of Defect-Engineered MOFs, a systematic summary of the defect formation mechanisms, synthetic strategies, and roles in biomedical applications is still lacking. This review systematically outlines the synthetic strategies for Defect-Engineered MOFs, discusses the relationships between the structure and performance, and highlights representative advances in drug delivery and all-in-one tumor therapeutic. Finally, we discuss the challenges regarding reproducibility and biocompatibility in the field, and propose future directions for promoting the clinical application of Defect-Engineered MOFs. (Figure presented.). Key Scientists: In 1989, Robson developed the first MOFs by varying the building blocks, specific substances can be captured and stored inside the cavities. Following pioneering work by Robson, around the turn of the 2000s, Kitagawa and Yaghi developed more flexible and stable MOFs, whose highly tunable and coordinatively flexible structure rapidly sparked widespread interest and laid the foundation for this rapidly expanding field of porous materials. In 1997, Lin and his coworkers researched coordination polymers. In 1998, they first reported a neutral three-dimensional iron coordination polymer. Since around 2004, the group has focused on biomedical applications of nanoscale MOFs. In 2006, Chen pioneered and validated the ligand-directed strategy, laying the foundation for the precise design of subsequent MOFs. In 2007, Bu reported a PCU-type MOF, achieving porosity and defect regulation. By 2008, Attfield used atomic force microscopy to reveal surface growth defects in HKUST-1, providing early insights into MOF crystallography defects, while Lillerud introduced the exceptionally stable UiO-66, a zirconium-based framework that later became a cornerstone material in both engineering and biomedical research. In the same year, Wang pioneered the design and regulation of colossal cages in ZIFs for gas storage. In 2009, Serre pioneered the flexible MIL series and systematically explored framework dynamics (breathing behavior), paving the way for applications in controlled drug delivery and other biomedical fields. A paradigm shift occurred in 2013 when Zhou directly demonstrated and quantified abundant missing-linker defects in UiO-66, establishing defects as a viable and powerful means of property modulation. In 2015, Fischer formally defined Defect Engineering as a core strategy for precisely tailoring MOF properties. Around 2016, Morris and coworkers developed effective top-down methods to controllably introduce and manipulate defects, strongly promoting defect-engineered MOFs in drug delivery research. In 2017, Forgan reported pioneering studies on MOF-based drug loading and controlled release; by 2020 his team achieved a major advance with defect-engineered systems enabling controlled co-delivery of multiple therapeutic agents. In 2019, Jiang used defect engineering to improve the catalytic performance of MOFs. In the same year, Zhao and collaborators introduced defect-engineered MOF nanozymes, significantly expanding MOF applications in catalytic nanomedicine, and later innovated asymmetric single-atom catalysis within defect-MOFs for synergistic tumor treatment. In 2020, Pang reported the introduction of quasi defects, to further enhance the enrichment and catalytic performance of MOFs. In the same year, Shi et al., reported MOF nanozymes for synergistic therapy. In 2021, Liu's team developed multifunctional theranostic platforms based on Defect-MOFs that seamlessly integrate imaging and therapy. In 2024, Ouyang pioneered the development of Defect-MOFs as nucleic acid hydrolase nanozymes. Most recently, in 2025, Leticia Hosta-Rigau and colleagues demonstrated defect-engineered MOFs for hemoglobin-based oxygen delivery, offering promising new approaches to relieve tumor hypoxia and reprogram the tumor microenvironment. Importantly, Zhao and Li et al. reported the design of MOF-based materials with multiple morphologies, providing a new approach for the design and application of novel Defect-MOFs. (Figure presented.).