Exploring the dynamic interactions of iron-carbohydrate complexes with human blood serum

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Intravenous iron-carbohydrate complexes are widely used nanomedicines for the treatment of iron deficiency anaemia, particularly in patients with conditions like chronic kidney disease, heart failure and inflammatory diseases. Despite the abundance of physicochemical characterization and clinical studies for these products, a clear evidence-based correlation between physicochemical properties and clinical outcome of iron-carbohydrate complexes is yet to be established. There is, nonetheless, clear evidence that the nano-bio interface determines the bio-response and mode of action. Here, the early interactions between iron-carbohydrate nanomedicines and blood components are investigated using time-resolved small-angle X-ray and neutron scattering (SAXS and SANS, respectively) under flow conditions enabled by a microfluidic device. Two clinically relevant iron-carbohydrate complexes with different carbohydrate ligand morphologies, iron sucrose (IS) and ferric carboxymaltose (FCM), were studied for their early interactions (down to minutes) with human serum albumin (HSA) and human blood serum (HBS). When mixed with HSA, IS showed rapid agglomeration behavior at the nanoscale, as evidenced by a characteristic up-turn in the low-q region of the scattering curves, whereas FCM showed much slower agglomeration. With HBS, IS displayed a similar agglomeration behavior to that observed with HSA. In contrast, FCM showed increasingly repulsive interactions amongst its clusters in blood serum, reflected by a characteristic down-turn in the low-q scattering, associated with improved colloidal stability. These results demonstrate that early nano-bio interactions are strongly formulation-dependent and governed by differences in the carbohydrate shell architecture. These findings provide a physicochemical framework for the design of future cell-based and mechanistic studies aimed at bridging physicochemical properties with clinical outcomes.