Exploring the Role of Shape and Size in Metal–Organic Framework–Mediated Ferroptosis

Metal–organic frameworks (MOFs) have been explored as drug delivery vehicles due to their structural tunability. Physical characteristics of MOFs including particle size and shape strongly influence cellular interactions and uptake. It is crucial for the rational design of drug carriers to optimize these parameters. Recent studies have reported that iron (Fe)-based MOFs can induce ferroptosis in cancer cells, that we hypothesized that their physical properties may directly affect ferroptotic efficiency. In this study, we synthesized four types of Fe-based MOFs (MIL-88(Fe)-NH2) with distinct shapes (octahedral and rod-shaped) and sizes (200 nm and 800 nm). Although all MIL-88(Fe)-NH2 exhibited the same crystalline structure and comparable specific surface areas, Rod-shaped MIL-88(Fe)-NH2 (~ 200 nm in size) exhibited approximately 4-fold higher cellular uptake after 2 h compared to octahedral counterparts (n = 3, p < 0.0001), resulting in 2-fold intracellular Fe accumulation (n = 3, p < 0.01) and a 1.5-fold elevation in lipid peroxidation (n = 4, p < 0.0001, at 50 µg/mL). These results may be associated with their smaller size, higher aspect ratio, and smaller contact angle, which together promote efficient cellular internalization. In contrast, large-sized MIL-88(Fe)-NH2 exhibited comparable ferroptotic responses regardless of their shape. These findings provide new insights into the shape- and size-dependent behavior of Fe-based MOFs and offer a rational strategy for the design of MOF-based nanocarriers for cancer therapy. Shape and size-controlled iron (Fe)-based MOFs enable accelerated intracellular Fe delivery and potent ferroptotic cancer cell death. The 200 nm sized- and rod-shaped MIL-88(Fe)-NH2 exhibit faster cellular uptake and stronger ferroptosis induction than octahedron-shaped MIL-88(Fe)-NH2