FAP‐Activatable Theranostic Agent Inhibiting VEGF Expression for Liver Fibrosis Therapy

Liver fibrosis (LF) is a representative fibrotic disorder for which effective therapies remain limited, and its progression is closely associated with angiogenesis mediated by vascular endothelial growth factor (VEGF). Controlled drug release remains a key challenge, and anti-VEGF therapy for LF has yet to be established clinically. To address this challenge, a polymeric nanomedicine integrated with protein-binding fluorophore (PBF) and bevacizumab (an angiogenesis inhibitor), named PNPB, that was activated by fibroblast activation protein (FAP), a biomarker of LF, was first communicated in this work. When the PNPB was transferred to pathological liver tissue, the FAP specially expressed by activated hepatic fibroblasts will destroy the activatable polymeric micelle, thereby releasing the internal PBF and bevacizumab for imaging and treatment of LF. The results demonstrated that PNPB not only can sense FAP with high sensitivity of 0.227 ng/mL in vitro, but also can inhibit VEGF expression to suppress aberrant angiogenesis in vivo. In vivo living imaging results further showed that LF was alleviated and the hepatic function was improved concurrently. Moreover, western blotting and immunohistochemical analysis showed that several kinds biomarkers associated with VEGF, including VEGF, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, Ki67, and CD31, were significantly suppressed following PNPB treatment, uncovering the potential molecular mechanism of LF. These findings suggest that the PNPB has the potential as a theranostic agent for LF, highlighting the FAP-activatable strategy could be applied to design intelligent nanomedicine for diseases characterized by FAP overexpression.