Ni‐Alginate Hydrogel Microspheres with Sustained Interleukin 2 Release to Boost Cytokine‐Based Cancer Immunotherapy

Abstract Interleukin 2 (IL2) is the first approved immunotherapeutic agent in cancer treatment. However, high‐dose IL2 administrated through intratumoral injection still spreads all over the body, causing serious systemic toxicity. Herein, an injectable nickel‐alginate hydrogel microsphere (Ni‐ALGMS) to allow effective loading of IL2 and its sustained release after intratumoral administration is reported. In this design, histidine (his)‐tagged IL2 is assembled into the Ni‐ALGMS via the coordination bonds between his‐tag and Ni²⁺. After injecting IL2‐loaded Ni‐ALGMSs (IL2@Ni‐ALGMSs) into the tumor, IL2 slowly releases over long periods, thereby avoiding the risk of cytokine storm happening in IL2 systemic administration. Applying such IL2@Ni‐ALGMSs for tumor model treatment can significantly increase the tumor infiltration of T lymphocytes, and effectively inhibit tumor growth, especially in combination with immune checkpoint inhibitors. This study presents a novel IL2 sustained‐releasing platform for tumor immunotherapy, which can also be conveniently applied in other cytokines‐based immunotherapies.