Extracellular vesicles: emerging therapeutic agents for liver fibrosis

Liver fibrosis is a progressive condition characterized by excessive scar tissue buildup, leading to impaired liver function and potentially cirrhosis. Despite advancements in treatment strategies, effective anti-fibrotic therapies remain an urgent unmet need. Recent research has identified extracellular vesicles (EVs) as promising therapeutic agents due to their ability to mediate intercellular communication and regulate key fibrotic pathways. This review aims to provide a comprehensive overview of the therapeutic potential of EVs in different in vitro and in vivo models of hepatic fibrosis, focusing on their natural effects and recent advancements in their engineering for enhanced efficacy. EVs can be derived from various cellular sources, including mesenchymal stromal cells (MSCs) and liverresident cells. Biological materials, including serum, breast milk, bacteria, and plants, also serve as EV sources. Among these, MSC-EVs stand out for their therapeutic potential, which can be significantly enhanced through preconditioning with inflammatory signals, pharmacological agents, or genetic engineering to improve EV quality and efficacy. Engineering techniques have further expanded EV applications, enabling their use as precise and effective drug-delivery vehicles. Approaches such as loading EVs with pharmacological compounds, designing customized EVs, and creating EV-liposome hybrids enable targeted delivery to activated hepatic stellate cells (HSCs), central drivers of fibrosis progression. These strategies enhance the efficacy of EV-based treatments. Both natural and engineered EVs regulate critical pathways of liver fibrosis development, including activation of HSCs, modulation of pro-fibrotic genes, extracellular matrix deposition, and programmed cell death. Additionally, EVs modulate immune responses, fostering a liver microenvironment conducive to repair and regeneration. Combining the natural regenerative properties of EVs with innovative engineering strategies provides highly targeted, effective treatment approaches to restore liver function and address the urgent unmet need for chronic liver disease therapies.