Fast assembly of 'clickable nanogels' for drug delivery.

Poly(α-glutamic acid) (PGA)-based nanogels (NGs) have garnered significant attention due to their biocompatibility, biodegradability, and potential to be functionalized. Recent advances in click chemistry, particularly strain-promoted azide-alkyne cycloaddition (SPAAC), enable the formation of nanogels under mild, metal-free conditions, preserving biocompatibility and avoiding contamination. In this work, we developed and optimized a protocol based on SPAAC click chemistry for the production of PGA-based NGs; moreover, we investigated their physicochemical properties, stability, and potential for drug delivery by encapsulating doxorubicin (Dox) as a model drug. The produced NGs showed high stability under various storage conditions, especially when containing the drug. We observed sustained drug release in various buffers or media, retention of drug functionality in cell cultures, and its transfer to cell nuclei with a delay of few hours with respect to the free drug. This click-chemistry-based method for NG production can be easily applied to produce different nanostructures, and the original or modified nanogels could serve as carriers not only for hydrophilic drugs, but also for proteins or other biomolecules in a variety of biomedical applications.