Bioresponsive Self-Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune-Related Adverse Events in Tumor Immunotherapy

Despite the immense potential of immune checkpoint blockade (ICB) therapy in tumor treatment, its widespread clinical application is currently limited by unsatisfactory curative effect and off-target adverse effect. Herein, an injectable sericin (SS)/silk fibroin (SF) recombinant hydrogel, termed SF-SS-SMC hydrogel, is developed to enable local delivery of anti-CD47 antibody (α CD47). The hydrogel displays self-reinforcement in high H₂O₂ concentration of tumor microenvironment (TME), as the SS/Fe²⁺ supramolecular nanocomplex (SS-SMC) inside the hydrogel converts H₂O₂ to reactive oxygen species (ROS), further triggering additional crosslinking among the SF polymers. Therefore, the SF-SS-SMC hydrogel has an in vivo retention time longer than 21 days and acts as a reservoir for the long-term sustained release of α CD47. More importantly, the SF-SS-SMC hydrogel itself efficiently regulates the remodeling of a protumor immunosuppressive TME to an antitumoral TME through switching of tumor-associated macrophages from an anti-inflammatory M2 phenotype to a proinflammatory M1 phenotype without additional drugs. Based on the combined effect of sustained α CD47 release and TME reprogramming, the SF-SS-SMC hydrogel has satisfactory immunotherapeutic effects in the treatment of local, abscopal, remitting, and metastatic tumors. Further advantages, including low cost of production, simple fabrication, and ease of use, make it promising for commercial mass production.