Drug‐Eluting Shear‐Thinning Hydrogel for the Delivery of Chemo‐ and Immunotherapeutic Agents for the Treatment of Hepatocellular Carcinoma

Abstract Hepatocellular carcinoma (HCC) is a malignant and deadly form of liver cancer with limited treatment options. Transcatheter arterial chemoembolization, a procedure that delivers embolic and chemotherapeutic agents through blood vessels, is a promising cancer treatment strategy. However, it still faces limitations, such as inefficient agent delivery and the inability to address tumor‐induced immunosuppression. Here, a drug‐eluting shear‐thinning hydrogel (DESTH) loaded with chemotherapeutic and immunotherapeutic agents in nanocomposite hydrogels composed of gelatin and nanoclays is presented as a therapeutic strategy for a catheter‐based endovascular anticancer approach. DESTH is manually deliverable using a conventional needle and catheter. In addition, drug release studies show a sustained and pH‐dependent co‐delivery of the chemotherapy doxorubicin (acidic pH) and the immune‐checkpoint inhibitor aPD‐1 (neutral pH). In a mouse liver tumor model, the DESTH‐based chemo/immunotherapy combination has the highest survival rate and smallest residual tumor size. Finally, immunofluorescence analysis confirms that DESTH application enhances cell death and increases intratumoral infiltration of cytotoxic T‐cells. In conclusion, the results show that DESTH, which enables efficient ischemic tumor cell death and effective co‐delivery of chemo‐ and immunotherapeutic agents, may have the potential to be an effective therapeutic modality in the treatment of HCC.