Cholesterol (Chol) enhances the packing and reduces the fluidity and permeability of lipid bilayers in liposome-mediated drug delivery. However, Chol is readily extracted from the bilayer by biomembranes, compromising stability and leading to premature payload leakage. This study introduces a Chol-modified sphingomyelin (SM) lipid bilayer (SM-Chol) that retains Chol's membrane-condensing ability. SM-Chol with a disulfide bond and longer linker significantly improves drug delivery by blocking Chol transfer and payload leakage, increasing the maximum tolerated dose of vincristine, improving pharmacokinetics and tumor delivery, and enhancing antitumor efficacy across various cancer models. SM-Chol shows promise as a universal platform for enhanced therapeutic delivery.

Zhiren Wang, Wenpan Li, Yanhao Jiang, Jonghan Park, Karina Marie Gonzalez, Xiangmeng Wu, Qing-Yu Zhang, Jianqin Lu