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.

Certain chemo drugs have been reported to potentially induce tumor-specific immune recognition by triggering immunogenic cell death (ICD), which provides a promising alternative way for cancer immunotherapy. However, the immunogenic effects of such treatments are still weak and robust systemic antitumor immune responses are rarely seen when these agents were used alone. Herein, we proposed a trinity immune enhancing nanoparticles (TIENs) for boosting antitumor immune responses of chemo agents. The TIENs was constructed with Food and Drug Administration (FDA) approved polylactic acid (PLA), canonical proton-sponging cationic polymer polyethyleneimine (PEI), and Toll-like receptor 9 (TLR9) agonist cytosine phosphate guanine oligodeoxynucleotide (CpG-ODN). In in vitro studies, the TIENs was proved to (1) promote antigen capturing, (2) antigen-presenting cells (APCs) activation, and (3) antigen cross-presentation. In in vivo studies, intratumorally injected TIENs greatly enhanced antitumor effect and robust immune responses of oxaliplatin and doxorubicin in murine CT26 and 4T1 tumor models, respectively. Furthermore, after decoration with a detachable shielding, the TIENs was proved to be effective in promoting the antitumor effects of chemo agents after intravenous injection. The combination of TIENs with clinically widely used chemo agents should be meaningful in boosting effective antitumor immune responses and cancer therapy.