Metal ion-driven assembly for constructing a metal–phenolic network nanoparticle-loaded hydrogel as a tumor photothermal-immunotherapy agent

The development of a fast and eco-friendly one-step synthesis method for constructing multifunctional hydrogels to eliminate postoperative residual tumor cells is highly required. In this work, Fe³⁺ ions were selected as inorganic cross-linkers to link gelatin (Gel) and protocatechuic acid (PA) for driving assembly process, and then to form gelatin-metal-polyphenol (GMP) hydrogel, Gel-Fe-PA. The <i>in situ</i>-formed metal-phenolic network nanoparticle (MPN NP) Fe-PA can effectively respond to NIR stimulation and then transform light energy into heat energy for inducing tumor cells apoptosis. Furthermore, damage-associated molecular patterns, including adenosine triphosphate (ATP), calreticulin (CRT) and high mobility group box-1 (HMGB1), will be released and captured by dendritic cells (DCs) to subsequently induce an immune response. <i>In vivo</i> local antitumor therapy results showed that the GMP hydrogel-mediated photothermal effect could effectively inhibit tumor tissue growth in the residual tumor bed. The distant tumor tissue growth could also be inhibited in a bilateral 4T1 tumor model. Considering there are so many types of reactions between polyphenols and metal ions, we believe this study provides a universal strategy for the <i>in situ</i> fabrication of an MPN NP-loaded hydrogel with advanced tumor photothermal-immunotherapy ability <i>via</i> a fast and eco-friendly one-step synthesis method.