Lactate Efflux Inhibition by Syrosingopine/LOD Co‐Loaded Nanozyme for Synergetic Self‐Replenishing Catalytic Cancer Therapy and Immune Microenvironment Remodeling
Sheng‐Ming Wu, Lehua Xu, Chenlong He, Peng Wang, Jingwen Qin, Fangfang Guo, Yilong Wang
Abstract
catalytic nanozyme carrier co-loading lactate oxidase (LOD) and a clinically-used hypotensor syrosingopine (Syr) are developed and delivered for synergetic cancer treatment by augmented self-replenishing nanocatalytic reaction, integrated starvation therapy, and reactivating anti-tumor immune microenvironment. The synergetic bio-effects of this nanoplatform stemmed from the effective inhibition of lactate efflux through blocking the monocarboxylate transporters MCT1/MCT4 functions by the loaded Syr as a trigger. Sustainable production of hydrogen peroxide by catalyzation of the increasingly residual intracellular lactic acid by the co-delivered LOD and intracellular acidification enabled the augmented self-replenishing nanocatalytic reaction. Large amounts of produced reactive oxygen species (ROS) damaged mitochondria to inhibit oxidative phosphorylation as the substituted energy supply upon the hampered glycolysis pathway of tumor cells. Meanwhile, remodeling anti-tumor immune microenvironment is implemented by pH gradient reversal, promoting the release of proinflammatory cytokines, restored effector T and NK cells, increased M1-polarize tumor-associated macrophages, and restriction of regulatory T cells. Thus, the biocompatible nanozyme platform achieved the synergy of chemodynamic/immuno/starvation therapies. This proof-of-concept study represents a promising candidate nanoplatform for synergetic cancer treatment.