Engineered Intelligent Microenvironment Responsive Prodrug Conjugates Navigated by Bioinspired Lipoproteins for Reversing Liver Fibrosis

Abstract Liver fibrosis (LF) is characterized by excessive production of reactive oxygen species (ROS), abnormal activation of hepatic stellate cells (HSCs), and subsequent extracellular matrix (ECM) deposition. The complexity of multiple interrelated pathways involved in this process makes it challenging for monotherapy to achieve the desired therapeutic effects. To address this issue, this study designs a ROS‐activated heterodimer conjugate (VTO) to collaboratively alleviate LF. Additionally, a biomimetic high‐density lipoprotein is utilized for encapsulation, resulting in the formation of PL‐VTO, which enables natural liver targeting. Once PL‐VTO is delivered to the fibrotic liver, it can respond and release both parent drugs upon encountering the high ROS microenvironment, effectively scavenge ROS, induce quiescence of activated HSCs, and reduce collagen deposition, ultimately reversing LF. Overall, this study presents a feasible and versatile nanotherapeutic approach to enhance the prodrug‐driven treatment of LF.