Metabolic Reprogramming by Dual-Targeted Biomimetic Nanoparticles for Enhanced Tumor Chemo-Immunotherapy

Cancer-associated fibroblasts (CAFs)-mediated metabolic support plays a vital role in tumorigenesis. The metabolic network between cancer cells and CAFs may serve as promising targets for cancer therapy. Here, aiming at targeted blockade of the metabolic support of CAFs to cancer cells, a cancer cell-activated fibroblast hybrid membrane-camouflaged nanocarrier is designed, which is coated on solid lipid nanoparticles containing chemotherapeutic paclitaxel (PTX) and glycolysis inhibitor PFK15. The biomimetic nanoparticles possess outstanding dual-targeted ability which can simultaneously target cancer cells and CAFs. The encapsulated glycolysis inhibitor PFK15 can prevent the glycolysis of cancer cells and CAFs at the same time, thus increasing the chemosensitivity of cancer cells and blocking the metabolic support of cancer cells by CAFs. The results show that the combination of PTX and PFK15 exhibits excellent synergistic effects and inhibits tumor growth effectively. Moreover, the biomimetic nanoparticles can obviously reduce the lactate production in the tumor microenvironment, leading to an activated immune response and enhanced tumor suppression. This work presents a facile strategy to destroy the metabolic network between cancer cells and CAFs, and provides a potential combined chemo-immunotherapy mediated by glycolysis.