Targeting the GTPase RAN by liposome delivery for tackling cancer stemness-emanated therapeutic resistance

Cancer therapeutic resistance as a common hallmark of cancer is often responsible for treatment failure and poor patient survival. Cancer stem-like cells (CSCs) are one of the main contributors to therapeutic resistance, cancer relapse and metastasis. Through screening from our in-house library of natural products, we found polyphyllin II (PPII) as a potent anti-CSC compound for triple-negative breast cancer (TNBC). To enhance anti-CSC selectivity and improve druggability of PPII, we leverage the liposome-mediated delivery technique for increasing solubility of PPII, and more significantly, attaining broader therapeutic window. Liposomal PPII demonstrates its marked potency to inhibit tumor growth, post-surgical recurrence and metastasis compared to commercial liposomal chemotherapeutics in the mouse models of CSC-enriched TNBC tumor. We further identify PPII as an inhibitor of the Ras-related nuclear (RAN) protein whose upregulated expression is correlated with poor clinical outcomes. The direct binding of PPII to RAN reduces TNBC stemness, thereby suppressing tumor progression. Our work offers a significance from drug discovery to drug delivery benefiting from liposome technique for targeted treatment of high-stemness tumor.