Caseinophosphopeptides Overcome Calcium Phytate Inhibition on Zinc Bioavailability by Retaining Zinc from Coprecipitation as Zinc/Calcium Phytate Nanocomplexes

Caseinophosphopeptides have shown great potential to increase zinc bioavailability from phytate-rich diets, but the mechanism of action remains unclear. Here, caseinophosphopeptides from a sodium caseinate hydrolysate dose-dependently retained zinc in solution against calcium phytate coprecipitation under physiologically relevant conditions. The 3 kDa ultrafiltration separation unveiled no added low-molecular-weight chelates of zinc and calcium by caseinophosphopeptides. Tyndall effect, dynamic light scattering measurements, transmission electron microscopy observation, electron diffraction pattern, X-ray diffraction spectrum, and energy-dispersive X-ray analysis demonstrated the caseinophosphopeptides-mediated formation of single-crystal zinc/calcium phytate nanocomplexes (Zn/CaPA-NCs) with a size and ζ-potential of 10-30 nm and -25 mV, respectively. Caseinophosphopeptides-stabilized Zn/CaPA-NCs were found to deliver bioavailable nanoparticulate zinc in mouse jejunal loop ex vivo model and polarized Caco-2 cells, and the treatments with specific inhibitors revealed that intestinal zinc absorption from Zn/CaPA-NCs invoked macropinocytosis, lysosomal release into the cytosol, and transcytosis. Overall, our study proposes a new paradigm for the benefit of caseinophosphopeptides for zinc bioaccessibility and bioavailability in phytate-rich diets.