Jet-Lagged Nanoparticles Enhanced Immunotherapy Efficiency through Synergistic Reconstruction of Tumor Microenvironment and Normalized Tumor Vasculature.

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.