Injectable Thermal-Protective Hydrogel Enables Curative Tumor Ablation via Chemo-Immunomodulation

Image-guided thermal ablation has been included in the National Comprehensive Cancer Network (NCCN) guidelines of multiple solid tumors. However, insufficient ablation of larger lesions and thermal injury adjacent to major organs and tissues limit its clinical application. Besides, sublethal hyperthermia at the margin of ablation can induce an immunosuppressive tumor microenvironment and increases recurrence risk. These physical and biological limitations are linked to each other. We developed an injectable hydrogel MR@CaP@HA with in situ thermal insulation and dual-responsive (pH/GSH) chemo-immunomodulatory delivery. MR@CaP@HA hydrogel can create a thermal insulation area with a thickness of about 5-10 mm after injection in situ, keeping the surrounding tissues under 45 °C during ablation. The disulfide-cross-linked hyaluronic acid (HA) network degrades in a glutathione (GSH)-dependent manner, inducing gel-liquid transition and controlled nanoparticle release. The released MR@CaP (calcium phosphate co-loaded with MIT and R848) nanoparticles disassemble in an acidic environment, delivering mitoxantrone (MIT) and resiquimod (R848) in a dual-responsive manner. This dual-responsive delivery system induces robust immunogenic cell death and dendritic cell maturation and achieves macrophage M1 rate of 95% in vitro and 35% in vivo. With coordinated thermal modulation and programmable drug release, the integrated therapy sterilizes residual tumor cells and achieves complete tumor eradication in 50% of animals. This work establishes a material-driven platform that overcomes thermal safety and immune resistance barriers, offering a translational strategy to enhance procedural safety and long-term efficacy.