Injectable tert-butylphenylacetic acid/acrylated β-cyclodextrin-based hydrogels for co-delivery of CAR-T cells and IL-15 in solid tumor therapy

Chimeric antigen receptor (CAR)-T cell therapy has shown great potential in treating hematologic malignancies, but its efficacy in solid tumors is limited by the immunosuppressive microenvironment and poor tumor infiltration. Hydrogels possess excellent local delivery capabilities, providing a supporting environment for adoptive cells and enhancing their tumor retention. Here, we report injectable supramolecular hydrogels composed of hyaluronic acid grafted with tert-butylphenylacetic acid (HA-TP) and acrylated β-cyclodextrin (AC-β-CD) for the co-delivery of CAR-T cells and IL-15. The hydrogels rapidly form a stable 3D network via host-guest interactions and acrylate photocrosslinking, providing a niche that retains and activates CAR-T cells. Interleukin (IL)-15 promotes CAR-T cell proliferation, leading to improved infiltration and antitumor cytotoxicity. In mouse models of B16-F10-ovalbumin (OVA) melanoma and B cell lymphoma, the hydrogels mediate the extensive infiltration of OVA-specific CD8⁺ T cells or CAR-T cells into tumors, effectively suppressing tumor growth. Furthermore, the hydrogels significantly promote the proportion of central memory T cells and effector memory T cells, which enables long-term antitumor effects. This hydrogel platform therefore provides a rational and effective approach to improve CAR-T cell therapy for solid tumors.