Abstract
Lactic acid (LA), an anaerobic glycolysis metabolite normally oversecreted by tumor cells, can inhibit the activity of T cells and stimulate the rapid proliferation and migration of tumor endothelial cells (TECs), thereby limiting the synergistic treatment efficiency of tumor immunotherapy and vascular normalization. Herein, Jet-lagged nanoparticles, apatinib (APA)-loaded TEC-targeting nanodrug (APA/MCP) and lonidamine (LND)-loaded tumor cell-targeting nanodrug (LND/MCA), are constructed to combine vascular normalization therapy and tumor cell metabolic treatment. APA/MCP can block VEGF/VEGFR2 to inhibit TEC proliferation and LND/MCA can inhibit LA efflux to remodel tumor acid metabolism. After treatment, Jet-lagged nanoparticles remarkably reduce the level of LA in tumor microenvironment (TME) through limiting LA efflux. Besides, the pericyte cell coverage ratio of tumor vasculature increased to 69%, which is significantly improved compared to the APA/MCP group (47%). Moreover, the results of in vivo pharmacodynamic studies show that after the above synergistic reconstruction of TME and normalized tumor vasculature, the therapeutic effect of programmed death 1 (PD-1) drug is improved 3-folds to that of the PD-1 group. Above all, the strategy in this paper may propose an innovative vision to facilitate the tumor immunotherapy through high-precision spatiotemporal delivery strategy of nanodrugs.