Integrin-Enriched Membrane Nanocarrier for the Specific Delivery of RGD-modified Relaxin Analog to Inhibit Pancreatic Cancer Liver Metastasis through Reversing Hepatic Stellate Cell Activation

Liver metastasis is common in patients with pancreatic cancer (PC) and is the leading cause of death associated with PC. Liver fibrosis induced by activated hepatic stellate cells (HSCs) creates a favorable metastatic microenvironment that promotes metastasis growth. B7-33, a therapeutic peptide (relaxin analog) that targets relaxin family peptide receptors on activated HSCs, inhibits the pSMAD2/3 signaling pathway and weakens the fibrogenic properties of activated HSCs. However, the short half-life and highly conserved nature of the B7-33 sequence limit its application in vivo. Here, B7-33 is modified with the cRGD sequence, which does not affect the efficacy of B7-33 and allows B7-33 to assemble into vascular endothelial cell membrane-derived vesicles by specifically interacting with integrin alpha(v)beta(3). These rationally designed vesicles (B7-33-HNPs) are able to prolong the half-life of B7-33 in vivo and accumulate in the liver to reverse HSCs activation. Moreover, B7-33-HNPs prevent the formation and growth of liver metastases in a mouse model of metastatic PC. This study proposes a feasible strategy for building a therapeutic peptide delivery system through specific interactions, serving as a reference for preventing liver metastasis of PC through the regulation of HSCs.