Bioresponsive Self-Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune-Related Adverse Events in Tumor Immunotherapy
Bioresponsive Self-Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune-Related Adverse Events in Tumor Immunotherapy
复制标题
生物响应性自我增强丝胶/丝素水凝胶用于缓解肿瘤免疫治疗中免疫相关的不良事件
DOI：
10.1002/adfm.202213867
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发表时间：
2023
影响因子：
19
通讯作者：
Kaiyong Cai
中科院分区：
文献类型：
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作者：
Shuangquan Gou;Weilin Meng;Adriana C. Panayi;Rong Wang;Rui Zhang;Pengfei Gao;Tingting He;Wenbo Geng;Shi Hu;Yongsheng Yu;Qian Feng;Kaiyong Cai
尽管免疫检查点阻断（ICB）疗法在肿瘤治疗中具有巨大的潜力，但其广泛的临床应用目前受到疗效不佳和脱靶不良反应的限制。本文中，开发了一种可注射的丝胶蛋白（SS）/丝素蛋白（SF）重组水凝胶（称为SF-SS-SMC水凝胶），以实现抗CD 47抗体（α CD 47）的局部递送。水凝胶在肿瘤微环境（TME）的高H2 O2浓度下显示出自增强，因为水凝胶内部的SS/Fe 2+超分子纳米复合物（SS-SMC）将H2 O2转化为活性氧（ROS），进一步引发SF聚合物之间的额外交联。因此，SF-SS-SMC水凝胶的体内保留时间超过21天，可作为α CD 47长期缓释的储库。更重要的是，SF‐SS‐SMC水凝胶本身通过将肿瘤相关巨噬细胞从抗炎M2表型转换为促炎M1表型，有效调节促肿瘤免疫抑制性TME向抗肿瘤TME的重塑，而无需额外药物。基于持续释放α CD 47和TME重编程的联合作用，SF-SS-SMC水凝胶在治疗局部、远端、缓解和转移性肿瘤中具有令人满意的免疫调节作用。进一步的优点，包括生产成本低，制造简单，易于使用，使其有希望的商业大规模生产。
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 H2O2concentration of tumor microenvironment (TME), as the SS/Fe2+supramolecular nanocomplex (SS‐SMC) inside the hydrogel converts H2O2to 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.