Emerging Nano Drug Delivery Systems Targeting Cancer-Associated Fibroblasts for Improved Antitumor Effect and Tumor Drug Penetration

Currently, clinically used antitumor nanomedicine is usually insufficient to eradicate malignancies, due to the tumor stroma exerting therapeutic resistance and physical barriers for proper drug delivery. As the most abundant cells in the tumor stroma, cancer-associated fibroblasts (CAFs) produce a critical tumor-promoting effect and barriers preventing the physical delivery of nanomedicines through secreting pro-tumorigenic cytokines, increasing solid tumor pressure and interstitial fluid pressure (IFP), and nonspecific internalization. Therefore, beyond treatment centered on cancer cells, researchers are focusing on targeting CAFs to fight stromal-rich tumors. In recent years, a series of novel nano delivery systems have been developed based on specific CAF-targeted ligands and advanced biofunctional materials. On the one hand, CAF-targeted nano delivery systems inhibit the pro-tumor signaling pathway between CAFs and cancer cells to reverse tumorigenesis, immunosuppression, or drug resistance in the tumor microenvironment, thus improving the sensitivity to antitumor treatments. On the other hand, nanostrategies acting on CAFs profoundly contribute to increasing the deep penetration of antitumor drugs through the decrease of solid pressure, IFP, and dense extracellular matrix generation related to the resistance to intratumoral diffusion. In this review, we first introduce the biological mechanisms of CAFs that interfere with nanotherapy. The state-of-the-art passive and active strategies of nano delivery systems targeting CAFs are then summarized, focusing on the therapeutic mechanism involved and the rational design of nano delivery systems. Additionally, the challenges of CAF-targeted nanotherapy are discussed from the perspectives of developing efficient nano delivery systems and potential clinical use.