Nanotechnology-based combinational strategies toward the regulation of myofibroblasts and diseased microenvironment in liver fibrosis and hepatic carcinoma

Liver fibrosis and hepatic carcinoma (HCC) pose a huge challenge worldwide due to the lack of effective treatment options for end-stage liver diseases. According to their functions and roles, hepatic myofibroblasts mainly include nontumoral fibroblasts (mainly activated hepatic stellate cells (HSCs)), which are involved in the wound-healing process of liver fibrosis, and cancer-associated fibroblasts (CAFs) in hepatic HCC. HSCs play a significant role in regulating extracellular matrix (ECM) deposition in progressive liver fibrosis. CAFs can be derived from activated HSCs and differentiate into ECM-producing myofibroblasts. Moreover, growing evidence shows that CAFs are the primary regulators of the HCC microenvironment, releasing growth factors and cytokines and suppressing the antitumor immune response. Combined therapeutic strategies show reduced drug resistance and side effects. Nanotechnology-based combined strategies aim to improve the delivery efficiency of various therapeutic agents with reduced toxicity via multiple mechanisms. In this review, we will discuss recent developments in combinational strategies based on nanotechnology that regulate myofibroblasts and the diseased microenvironment for liver fibrosis and HCC treatment. We will also identify the major challenges that the field is facing and offer some insights for future drug discovery.