Metal-Coordinated His-Tag Functionalization of Polymeric Nanogels for Therapeutic Applications

Nanogels (NGs) are versatile polymeric nanocarriers with high drug loading capacity and colloidal stability, making them pivotal candidates for targeted biomedical applications. Surface functionalization with biomolecules is essential for selective targeting therapies; however, conventional covalent conjugation can compromise the activity of sensitive ligands (e.g., proteins and antibodies). The His-tag strategy offers a reversible, oriented binding through coordination with transition metal ions, widely used in protein purification, but scarcely explored for polymeric NG decoration. Here, we developed polyallylamine-based NGs via an emulsion-evaporation process. The NG outer layer was functionalized with lysine-conjugated nitrilotriacetic acid to chelate Ni²⁺ or Co³⁺ ions, enabling the His-tag strategy. To validate this approach, a His-Rhodamine compound was used as a representative His-tag structure, mimicking potential bioactive ligands or motifs. Our results demonstrate that Co³⁺ provides superior His-tag grafting density compared to Ni²⁺, preserving the biocompatibility of the nanoscaffold. The cobalt-complexed NGs were also tested as cisplatin delivery systems, showing enhanced therapeutic performance compared with the administration of the free drug in ovarian cancer cells. Overall, the cobalt-mediated His-tag conjugation proved to be an efficient approach for the noncovalent surface decoration of polymeric NGs, defining a reliable alternative for the functionalization of this type of nanoscaffolds. Owing to the presence of His-tag functionalities in several biomolecules, the proposed strategy can be readily extended to a wide range of His-tag-based species, thus providing a flexible platform for the design of advanced, targeted NGs with improved selectivity and therapeutic potential.