Regulation of Interstitial Fluid Pressure for Improved Intratumor Drug Permeability and Nanozyme-Enhanced Chemocatalytic Therapy

The extremely low delivery efficiency of nanomedicine is an important obstacle in the process of tumor therapy, which is mainly caused by the abnormally high tumor interstitial fluid pressure (TIFP) in the tumor microenvironment. This is due to the tumor being short of the lymphatic system, resulting in the lymphatic drainage being blocked. The retained interstitial fluid raises TIFP, leading to the formation of a reverse pressure difference between the tumor tissue and blood vessels, which blocks the delivery of blood-borne drugs to the center of the tumor. Herein, we designed a ZnO–Au/CLM nanomedicine delivery system focusing on reducing TIFP, which is composed of ZnO–Au, bis(2,4,5-trichloro-6-carboxyphenyl) oxalate, liposome, and tumor cell membrane. The drugs were delivered to the tumor through cell membrane homologous targeting and then bis(2,4,5-trichloro-6-carboxyphenyl) oxalate reacted with hydrogen peroxide (H2O2) to generate high-energy intermediates 1,2-dioxetanedione, which activated the splitting water of ZnO to produce hydrogen and hydroxyl radical (•OH) for chemocatalytic treatment. Therefore, the volume of tumor interstitial fluid was reduced, thereby decreasing TIFP and enhancing the delivery of drugs to the depth tumor. As nanozyme Au NPs could effectively catalyze glucose to generate H2O2, which not only starved the tumor cells but also supplied H2O2 for chemocatalytic therapy. After 120 min of ZnO–Au/CLM treatment, the relative TIFP decreased to 59.16% in tumor-bearing mice, meanwhile, the drug accumulation in the tumor increased by 10.4 times compared with the control group. This work leads to a new direction of catalytic medicine by combining nanomedicine with catalysis.