Thermoresponsive Chitosan Nanocomposite-Based Double-Network Hydrogel for Sustained Tumor Immunotherapy

Long-term tumor immunotherapy remains challenging due to poor drug retention and immune activation. Here, we proposed a chitosan-based composite hydrogel capable of in situ gelation at physiological temperature to form a durable depot for sustained and tumor microenvironment (TME)-responsive release. The system integrated indocyanine green (ICG)-loaded gold nanorods within boronic acid-modified mesoporous silica (GSB) and thermoresponsive nanocomposites (ICG@GAN), which were further loaded with β-glycerophosphate (β-GP) and genipin and embedded in a carboxymethyl chitosan matrix. Upon injection, sequential release of β-GP and genipin triggered rapid physical and stable chemical cross-linking, forming a high-strength double-network hydrogel. Gradual leaching of β-GP, along with enzymatic degradation of chitosan, sustained the release of ICG@GAN. In the TME, cleavage of boronate esters triggered the release of ICG and GSB, enabling synergistic photothermal and ROS-mediated tumor cell apoptosis and tumor-associated macrophage repolarization. Meanwhile, chitosan modulated the immune feedback to amplify immune activation and infiltration. This integrated hydrogel platform markedly suppressed tumor growth and metastasis, offering a promising strategy for long-term immunotherapy.