Hyaluronic Acid Hydrogel Implants for Sustained Release of Oxaliplatin and Resiquimod to Prevent Hepatocellular Carcinoma Recurrence Post‐Radiofrequency Ablation

Abstract Hepatocellular carcinoma (HCC) remains a global challenge due to limited therapies and high recurrence. While radiofrequency ablation (RFA) is commonly used, its efficacy is hindered by incomplete ablation. Local immunotherapy has gained attention as a novel strategy to improve therapeutic efficacy through targeted activation of anti‐tumor immunity. In this work, a biopolymer implant (BI) hydrogel based on hyaluronic acid is developed for the sustained release of oxaliplatin (OXA) and resiquimod (R848), aiming to enhance the immunotherapeutic efficacy of RFA in liver cancer. The injectable BI hydrogel, formed via Schiff base linkage, enables prolonged drug release and exhibits favorable biosafety. In subcutaneous HCC models, RFA + BI(OXA + R848) achieved 97.1% tumor inhibition and 40% complete remission. Additionally, the combination therapy is further validated in bilateral tumor and orthotopic HCC models, demonstrating superior tumor suppression. Furthermore, flow cytometry and RNA sequencing confirmed that RFA combined with BI(OXA + R848) significantly enhanced intratumoral dendritic cell activation, promoted the recruitment of CD8⁺ T lymphocytes and NK cells, and induced robust immune memory. This synergistic engagement of the innate‐adaptive immune axis underscores its potential to address challenges in both local tumor control and systemic recurrence prevention.