Engineered exosomes loaded with M1–8 peptide for targeted therapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent and highly malignant tumor malignancies worldwide and is characterized by poor prognosis and high mortality. Therefore, effective medications are urgently needed to improve therapeutic effects with HCC. Exosomes are nanoscale vesicles that can transfer cellular information. Owing to their excellent biocompatibility, exosomes are frequently utilized as drug carriers for cancer treatment. Targeted drug delivery systems that modify exosomes to increase targeting have emerged as promising therapeutic platforms in response to the lack of precise targeting by natural exosomes. In this study, HTPP-Exo was successfully constructed by modifying the exosome membrane by connecting sulfhydryl group of HTPP with maleimide in DSPE-PEG2000-Mal, and the antimicrobial peptide M1–8 was included for the first time through co-incubation, thus successfully establishing the HTPP-Exo-M1–8 targeted drug delivery system. The targeting ability of HTPP-Exo-M1–8 was verified by evaluating its in vitro and in vivo targeting of HepG2 cells, and its therapeutic ability was evaluated by its inhibitory effect on HepG2 cells and in situ liver cancer in mice. The results showed that HTPP-Exo-M1–8 targeted drug delivery system could target HepG2 cells in vivo and in vitro, and the survival rate of HepG2 cells was 45 % after HTPP-Exo-M1–8 treatment for 48 h. After in vivo treatment, the volume of HCC in HTPP-Exo-M1–8 group (270.4 mm3) was much smaller than that in control group (969.5 mm3), which achieved the expected purpose of HCC treatment. Further research showed that the targeted drug delivery system HTPP-Exo-M1–8 could be used to treat HCC by inhibiting the lysosome–autophagosome fusion in HepG2 cells. Additionally, there was no obvious toxicity to healthy cells or tissues when HTPP-Exo-M1–8 was used. Overall, the exosome-based targeted drug delivery system HTPP-Exo-M1–8 can treat HCC by targeting and penetrating tumor cells, which provides a new strategy for the treatment of HCC.