Engineering of liposomes containing cholesterol analogues to enhance melanoma therapy via membrane fusion

A key challenge in disease treatment and prevention is the efficient delivery of therapeutics to the cells. To address this, a primary strategy is the use of liposomes to protect the payload and enhance cellular uptake. However, the delivery efficiency of traditional liposomes remains limited, as cellular internalization primarily occurs through endocytosis. Here, we present a strategy to engineer liposomes with Cholesterol analogues to enhance delivery efficiency via membrane fusion. Liposomes containing Cholesterol analogues including β-sitosterol (Sito/Lip) and stigmasterol (Stig/Lip) show a 3-fold higher uptake by melanoma cells. Mechanistically, we have demonstrated that Sito and Stig increase the fluidity and hydrophobicity of the Liposome membranes, thereby promoting liposome-cell membrane fusion and uptake by melanoma cells. Using doxorubicin (DOX) as a model drug, we have shown that Sito/Lip and Stig/Lip loaded with DOX significantly induce tumor cell Apoptosis. In vivo, the Stig/Lip loaded with DOX has significant antitumor efficacy, reducing tumor weight by up to 4-fold compared to the traditional liposomes containing Cholesterol. Furthermore, the Stig/Lip loaded with DOX demonstrates excellent biocompatibility. Thus, our findings provide an effective strategy for melanoma therapy and present a generalizable method for enhancing cellular uptake through membrane fusion.