Mitigating metal-organic framework (MOF) toxicity for biomedical applications

[Display omitted] •MOFs are classified based on their toxicity level in this review.•Physico-chemical factors such as chemistry, particle size, and morphology influence MOF toxicity.•Surface modification strategies enhance MOF cytocompatibility (in vitro) and biocompatibility (in vivo)•MOFs demonstrate promising potential for numerous biomedical applications.•Safe MOFs are essential for clinical translatability. Metal-organic frameworks (MOFs) are a novel class of crystalline porous materials, consisting of metal ions and organic linkers. These hybrid materials are highly porous and have a large specific surface area, making them of great interest for applications in gas separation, energy storage, biomedical imaging, and drug delivery. As MOFs are being explored for biomedical applications, it is essential to comprehensively assess their toxicity. Although nearly ninety thousand MOFs have been investigated, evaluating and optimizing their physico-chemical properties in relevant biological systems remain critical for their clinical translation. In this review article, we first provide a brief classification of MOFs based on their chemical structures. We then conduct a comprehensive evaluation of in vitro and in vivo studies that assess the biocompatibility of MOFs. Additionally, we discuss various approaches to mitigate the critical factors associated with MOF toxicity. To this end, the effects of chemistry, particle size, morphology, and particle aggregation are examined. To better understand MOFs' potential toxicity to living organisms, we also delve into the toxicity mechanisms of nanoparticles (NPs). Furthermore, we introduce and evaluate strategies such as surface modification to reduce the inherent toxicity of MOFs. Finally, we discuss current challenges, the path to clinical trials, and new research directions.