Enzyme-based hollow downconversion nanoparticle for adaptively remodeling tumor acidic microenvironment and augmenting chemotherapy

Abstract

The abnormal metabolism of rapidly growing tumors can create an acidic tumor microenvironment (TME) that renders cancer cells resistant to chemotherapy. Adaptive pH-elevating nanoparticles that can maintain pH within a reasonable range would enhance the efficacy of chemotherapy. Here, pH-elevating, enzyme-based nanoparticles were constructed to remodel the TME and enhance tumor chemotherapy. Hollow NaBiF₄:Nd nanoparticles were engineered for drug delivery encapsulated paclitaxel and the urea substrate. They were coated with polyacrylic acid to confer acid responsiveness and were conjugated with urease on their surface. The resulting nanoparticles (BUPAU') effectively shift the pH from acidic to neutral or alkaline in aqueous environments. Concurrently, concurrent degradation of NaBiF₄:Nd provides real-time fluorescence feedback. Importantly, in vitro and in vivo data of the urease-urea system reveal that the nanoparticles effectively neutralize the acidic TME pH, sensitizing cancer cells to subsequent chemotherapy. Thus, compared to chemotherapy alone, the therapy by remodeling the TME significantly improves the antitumor effect of paclitaxel in vitro and in vivo. The findings demonstrate that chemotherapy sensitization could be synchronized by modulating TME pH.