3D printing combined with pH-induced 4D printed iron(III)-oxidized starch gels for controlled iron delivery and enhanced iron supplementation.

Iron deficiency anemia (IDA) necessitates effective iron supplementation with high bioavailability and controlled release. This study developed 4D-printed ferric-oxidized starch gels (4D-FeOMS) as a stimulus-responsive platform for targeted iron delivery. By combining hot-extrusion 3D printing with pH-triggered 4D transformation, Fe3+ was effectively coordinated within oxidized starch networks via ionic crosslinking. Rheological analysis revealed Fe3+ hydrolysis disrupted starch molecular hydrogen bonding and reducing molecular weight, leading to diminished gel network uniformity and density. Compared to 3D-printed samples (3D-FeOMS), 4D-FeOMS exhibited red-shifted CO FTIR peaks, lower Fe 2p XPS binding energies, and reduced correlation length (ξ), indicating improved molecular entanglement and network uniformity. In vitro digestion demonstrated gastric resistance (<30 % Fe3+ release) and rapid iron release (>85 %) in the proximal small intestine. In vivo evaluation in IDA mice showed that 4D-FeOMS significantly restored biochemical and hematological parameters, increased organ iron stores (restored >94.6 %), and enhanced antioxidant enzyme activity, outperforming iron salts and 3D-FeOMS. Mechanistically, 4D-FeOMS optimized hepcidin expression and regulated ferritin/transferrin levels, facilitating systemic iron transport. Notably, 4D-FeOMS-10 % demonstrated iron supplementation efficacy performance due to the appropriate iron addition and optimal Fe3+ complexation. These findings highlighted the potential of 4D-printed starch-based platforms as intelligent mineral delivery systems for treating micronutrient deficiencies.