Ferritin‐Based Nanocomposite Hydrogel Promotes Tumor Penetration and Enhances Cancer Chemoimmunotherapy

Abstract Hydrogels are prevailing drug delivery depots to improve antitumor efficacy and reduce systemic toxicity. However, the application of conventional free drug‐loaded hydrogel is hindered by poor drug penetration in solid tumors. Here, an injectable ferritin‐based nanocomposite hydrogel is constructed to facilitate tumor penetration and improve cancer chemoimmunotherapy. Specifically, doxorubicin‐loaded human ferritin (Dox@HFn) and oxidized dextran (Dex‐CHO) are used to construct the injectable hydrogel (Dox@HFn Gel) through the formation of pH‐sensitive Schiff‐base bonds. After peritumoral injection, the Dox@HFn Gel is retained locally for up to three weeks, and released intact Dox@HFn gradually, which can not only facilitate tumor penetration through active transcytosis but also induce immunogenic cell death (ICD) to tumor cells to generate an antitumor immune response. Combining with anti‐programmed death‐1 antibody (αPD‐1), Dox@HFn Gel induces remarkable regression of orthotopic 4T1 breast tumors, further elicits a strong systemic anti‐tumor immune response to effectively suppress tumor recurrence and lung metastasis of 4T1 tumors after surgical resection. Besides, the combination of Dox@HFn Gel L with anti‐CD47 antibody (αCD47) inhibits postsurgical tumor recurrence of aggressive orthotopic glioblastoma tumor model and significantly extends mice survival. This work sheds light on the construction of local hydrogels to potentiate antitumor immune response for improved cancer therapy.