Hyaluronidase nanogel-armed CAR-T cell for synergistically reducing tumor extracellular matrix and improving efficacy against solid tumors

The application of chimeric antigen receptor T (CAR-T) cell therapy against solid tumors is often hindered by the dense and rigid tumor extracellular matrix (ECM). While combining CAR-T with hyaluronidase (HAase) to reduce ECM is apparent, the efficacy is limited because of low accumulation and penetration efficiency of HAase inside the tumor tissue. Herein, we report a stimuli-responsive HAase-loaded nanogels (H-NGs) which are conjugated on the surface of CAR-T cells for synergistically improving HAase accumulation, ECM degradation and CAR-T cell efficacy. The conjugation of H-NGs on the T cell surface was achieved through metabolic oligosaccharide engineering (MOE) in a semi-quantitatively controlled manner. Intravenous injection of H-NGs armed CAR-T cells resulted in more ECM degradation than co-injection of CAR-T cells and free H-NGs, leading to an 83.2% tumor inhibition rate and relieving tumor suppressive microenvironment in the Raji solid tumor model. Proteomic analysis of the harvested tumor tissues indicated that the combining of H-NGs and CAR-T cell collaboratively reduces cell adhesion and enhanced leukocyte transendothelial migration. Overall, this work simultaneously boosts the efficacy of hyaluronidase and CAR-T cells in combating solid tumor, which has broad application potential in cancer combination therapy.