Engineered exosomes from umbilical cord mesenchymal stem cells with pPB modification attenuate hepatic fibrosis via hepatic stellate cell targeting

Current therapeutic strategies for hepatic fibrosis remain limited, primarily due to lack of effectively targeting activated hepatic stellate cells (aHSCs) without compromising treatment safety. Although human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) exhibit promising therapeutic potential, their clinical application is constrained by rapid clearance via the mononuclear phagocyte system (MPS) and inadequate target specificity. This study aimed to develop engineered exosomes with enhanced targeting capabilities toward aHSCs through surface modification, thereby improving their anti-fibrotic efficacy. We developed an exosomal delivery system modified with a pPB cyclic peptide (hUCMSC-Exos@pPB) using DSPE-PEG-NH2-based nanoengineering to enable specific targeting of aHSCs. The targeting efficiency of hUCMSC-Exos@pPB was assessed via in vivo imaging and immunofluorescence co-localization analysis with α-smooth muscle actin (α-SMA). Biosafety of the hUCMSC-Exos@pPB delivery system was comprehensively evaluated through CCK-8 assays in vitro, hematoxylin and eosin (HE) staining of major organs in experimental animals, and the analysis of liver and kidney function indicators. The anti-liver fibrosis efficacy of hUCMSC-Exos@pPB was evaluated through multiple approaches, including histopathological assessments (HE, Masson, and Sirius red staining), oxidative stress markers (malondialdehyde and NADPH oxidase 4), measurement of liver function parameters (aspartate aminotransferase and alanine aminotransferase), and analysis of fibrogenic protein expression (α-SMA and COL1a1) in vivo and in HSC-T6 cells. Transcriptome RNA sequencing of liver tissue revealed the PI3K-Akt signaling pathway as a pivotal mechanism through which hUCMSC-Exos@pPB exerts its anti-fibrotic effects. Through rational surface engineering with pPB peptide ligands, we developed a novel exosomal nanoplatform that effectively evades clearance by the MPS and achieves targeted delivery to aHSCs. This strategy significantly enhanced the therapeutic efficacy of hUCMSC-Exos against hepatic fibrosis, therey providing a promising translational approach for the precision treatment of chronic liver diseases.