Unravelling Cytotoxicity Profile Differences in Structurally Similar Metal-Organic Frameworks

Metal-organic frameworks (MOFs) have emerged as highly tunable nanomaterials with significant promise for biomedical applications, but their cytotoxicity profiles vary considerably across structural variants. This review synthesises comparative studies of structurally similar MOFs to establish structure-toxicity relationships, where such MOFs variants are defined as frameworks differing only by one key parameter, such as metal node, linker chemistry, surface functionalisation, or particle size. Evidence consistently shows that the choice of metal node is the primary determinant of toxicity. Frameworks based on redox-inert metals, including Zr, Al, and Cr, exhibit high stability and favourable biocompatibility, whereas MOFs incorporating Cu or Mn nodes often induce cytotoxicity through redox cycling and reactive oxygen species (ROS) generation. Linker chemistry further modulates toxicity by influencing polarity and hydrolytic stability. For example, fumarate and 1H-imidazole-2-carbaldehyde (HICA) linkers promote rapid degradation and oxidative stress, while aromatic linkers such as trimesic acid, terephthalic acid, and biphenyldicarboxylate provide enhanced stability and lower toxicity. Surface functionalisation introduces cell-type-specific effects: amine or nitro groups can enhance uptake and ROS generation, while hydrophobic modifications alter aggregation behaviour and circulation time. Particle size also plays a dual role, with nanoscale particles increasing dissolution-driven toxicity and larger micron-sized particles exerting mechanical stress on cells. Collectively, these findings highlight how subtle structural differences critically shape the biological behaviour of MOFs. By mapping these structure–toxicity relationships, this review provides mechanistic insights and design principles to guide the safe and effective development of MOFs for biomedical use.