A CuS-Based Nanoplatform Catalyzing NO Generation for Tumor Vessel Improvement and Efficient Chemotherapy

Vascular normalization, which aims to improve the tumor vascular structure and function, is an efficient way to improve the perfusion and penetration of tumors in cancer therapy. Recently, researchers reported that nitric oxide (NO) delivery could normalize tumor vascular because of its property of regulation of angiogenesis and vessel maturation. However, this effect is limited by the limited release time and quantity. In the current study, to achieve a sustainable and stable NO supply for vascular improvement, an l-selenocysteine modified DOX loading copper sulfide (CuS) nanocatalytic system (dCuS-SeCA NPs) was constructed to produce NO at tumor sites by catalyzing the reaction with an endogenous NO donor, nitrosoglutathione (GSNO), in situ. After improving vessels, dCuS-SeCA NPs released DOX with an 808 nm laser for effective tumor inhibition. The catalysis of NO experiments showed that dCuS-SeCA NPs could catalyze the decomposition of GSNO to generate NO in vitro and in vivo, which inhibited the expression of VEGFA, EGF, and ANGPT2 simultaneously in human umbilical vein endothelial cells (HUVECs), promoting vascular normalization. Additionally, dCuS-SeCA NPs could improve tumor perfusion 12 h after injection, which lasted for more than 6 days. Six days after injection, the effective perfusion (Hoechst 33342+) area was 5.9 times that of the untreated set. The tumor inhibition rate of dCuS-SeCA NPs with the 808 nm laser was up to 87.4%, better than that of dCuS (67.1%). Collectively, our findings provide a way for a sustainable NO supply for tumor vascular normalization to enhance the anticancer effect.