Development and efficacy evaluation of nanoliposomes targeting CAFs-LCSCs communication for hepatocellular carcinoma treatment.

•.CAP@CD133-D/X-Lip was constructed. • CAP@CD133-D/X-Lip inhibits metastasis and recurrence of HCC. Hepatocellular carcinoma (HCC) is a prevalent global malignancy, presenting significant challenges in developing safe and effective treatments to prevent recurrence. This is mainly attributed to the inability of traditional treatments to eliminate liver cancer stem cells (LCSCs). LCSCs exhibit resistance to standard therapies, such as radiotherapy and chemotherapy, playing a noticeable role in drug resistance, metastasis, and recurrence of HCC. Their "stemness" is maintained by cancer-associated fibroblasts (CAFs), especially dense CAFs that form a barrier, hindering drug delivery. These two components interact to drive the progression of HCC. Regarding this unique tumor microenvironment, a novel nanoliposome (CAP@CD133-D/X-Lip) was developed. This nanoliposome could initially target CAFs by leveraging fibroblast activating protein (FAP) overexpression on their surface, activating CAP-degrading peptides upon reaching CAFs. Subsequent size reduction and exposure of CD133 aptamers enable secondary targeting of LCSCs, leading to the release of the antitumor drug doxorubicin hydrochloride (DOX) and the LCSCs' inhibitor XAV-939 in deep tumor regions. The efficacy of CAP@CD133-D/X-Lip was validated in vitro and in vivo , demonstrating its ability to target therapeutic drugs and disrupt the 'CAFs-LCSCs' communication, thereby slowing HCC progression and enhancing treatment outcomes. This approach holds significant promise for the clinical management of HCC. [ABSTRACT FROM AUTHOR]