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The immune checkpoint blockade of programmed death ligand-1 (PD-L1) or programmed death-1 (PD-1) has been a promising strategy to restore T cell mediated tumor suppression. In this study, a plasmid DNA which expressed small hairpin RNA of PD-L1 (shPD-L1) was loaded in the ultrasensitive pH triggered charge/size dual-rebound P[(GP)D] nanoparticles (NPs) to silence the PD-L1 gene for reducing the PD-L1/PD-1 interactions between tumors and T cells. To increase the penetration of the shPD-L1 loaded P[(GP)D] NPs (shPD-L1@NPs) in tumors, hyaluronidase (HAase) was utilized to degrade the overexpressed hyaluronicacid (HA) in the extracellular matrix (ECM) of the tumor tissues. The HAase-enhanced tumor accumulation and penetration of the P[(GP)D] NPs were carefully explored. Further in vivo antitumor therapy was carried out in the malignant melanoma mouse tumor model, and a significant tumor inhibition effect was achieved by the combination treatment of HAase and shPD-L1@NPs. Our results verified that the HAase could effectively degrade the HA in tumors and increase the penetration of the shPD-L1@NPs for achieving more efficient PD-L1 gene silence and finally realizing potent tumor suppression. This combination treatment strategy has great potentials to be adopted for other nanomedicines, and it will have broad applications for cancer therapy in the future.