Carrier-Free\nNanoagent Interfering with Cancer-Associated\nFibroblasts’ Metabolism to Promote Tumor Penetration for Boosted\nChemotherapy

Elevated\nproduction of extracellular matrix (ECM) in tumor stroma\nis a critical obstacle for drug penetration. Here we demonstrate that\nATP-citrate lyase (ACLY) is significantly upregulated in cancer-associated\nfibroblasts (CAFs) to produce tumor ECM. Using a self-assembling nanoparticle-design\napproach, a carrier-free nanoagent (CFNA) is fabricated by simply\nassembling NDI-091143, a specific ACLY inhibitor, and doxorubicin\n(DOX) or paclitaxel (PTX), the first-line chemotherapeutic drug, via\nmultiple noncovalent interactions. After arriving at the CAFs-rich\ntumor site, NDI-091143-mediated ACLY inhibition in CAFs can block\nthe de novo synthesis of fatty acid, thereby dampening the fatty acid-involved\nenergy metabolic process. As the lack of enough energy, the energetic\nCAFs will be in a dispirited state that is unable to produce abundant\nECM, thereby significantly improving drug perfusion in tumors and\nenhancing the efficacy of chemotherapy. Such a simple drug assembling\nstrategy aimed at CAFs’ ACLY-mediated metabolism pathway presents\nthe feasibility of stromal matrix reduction to potentiate chemotherapy.