Controlled Ionic Nanoaggregation by Microfluidics for the Continuous Production of Alginate Nanogels

Alginate nanogels are promising carriers for drug delivery owing to their biocompatibility, high water content, and mild ionic gelation process. However, conventional fabrication methods frequently rely on emulsion-based approaches involving surfactants and organic solvents, which may compromise their suitability for biomedical applications. In this work, a fully aqueous microfluidic strategy was developed to produce alginate nanogels through controlled ionic nanoaggregation of preformed polymer chains, avoiding the need for emulsion-based processing, surfactants, and organic solvents. The influence of hydrodynamic conditions, including total flow rate, flow rate ratio, and residence time, together with alginate and calcium chloride concentrations, was systematically investigated to elucidate the factors governing nanoaggregation, ionic crosslinking, and nanogel formation. The results demonstrate that nanogel properties depend on the interplay between mixing efficiency and crosslinking kinetics, defining an operating window in which small nanogels can be formed while minimizing uncontrolled aggregation. Under optimized conditions, nanogels with characteristic diameters below 60 nm were obtained by Cryo-SEM, although DLS measurements revealed the presence of larger aggregates in suspension. Comparison with conventional batch synthesis further demonstrated the advantages of the microfluidic approach in controlling nanogel formation and reducing aggregation. Finally, the optimized nanogels were used as confined reaction compartments for the in situ formation of palladium nanostructures through carbon monoxide-mediated reduction under mild conditions. Their characterization confirmed the formation of palladium nanosheets within the alginate matrix, demonstrating the potential of the platform for developing functional hybrid nanomaterials. This work establishes a microfluidic approach for controlling ionic nanoaggregation during nanogel formation and provides a versatile route towards functional alginate-based materials for biomedical applications.