Injectable Supramolecular Hydrogels for In Situ Programming of Car‐T Cells toward Solid Tumor Immunotherapy

Chimeric antigen receptor (CAR)‐T cell immunotherapy is approved in the treatment of hematological malignancies, but remains far from satisfactory in solid tumor treatment due to inadequate intra‐tumor CAR‐T cell infiltration. Herein, an injectable supramolecular hydrogel system, based on self‐assembly between cationic polymer mPEG‐PCL‐PEI (PPP) conjugated with T cell targeting anti‐CD3e f(ab')2 fragment and α‐cyclodextrin (α‐CD), is designed to load plasmid CAR (pCAR) with a T cell specific CD2 promoter, which successfully achieves in situ fabrication and effective accumulation of CAR‐T cells at the tumor site in humanized mice models. More importantly, due to this tumor microenvironment reprogramming, secretion of cellular inflammatory cytokines (interleukin‐2 (IL‐2), tumor necrosis factor‐α (TNF‐α), and interferon‐γ (IFN‐γ)) or tumor killer protein granzyme B is significantly promoted, which reverses the immunosuppressive microenvironment and significantly enhances the intra‐tumor CAR‐T cells and cytotoxic T cells infiltration. To the best of the current knowledge, this is a pioneer report of using injectable supramolecular hydrogel for in situ reprogramming CAR‐T cells, which might be beneficial for solid tumor CAR‐T immunotherapy. An injectable CAR plasmid (pCAR)‐loaded supramolecular hydrogel system for long‐term and sustained reprogramming of CAR‐T cells in situ for solid tumor immunotherapy is introduced. After injection locally adjacent to a solid tumor, the supramolecular hydrogel platform produces in situ CAR‐T cells by sustaining release of T cell‐targeting nanocomplexes‐carrying pCAR and significantly diminishes the immunosuppressive microenvironment or facilitates the clearance of solid tumors.