Optimization of lipid variants in lipid-PEG conjugates for triple-negative breast cancer cell surface modification

Abstract

Triple-negative breast cancer (TNBC) is defined by the absence of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor 2 (HER2), which contributes to its poor prognosis. Due to the lack of these receptors, available treatment options are limited, and the risk of early relapses is heightened. To address this challenge, a cell surface modification strategy was implemented to present an artificial receptor on the surface of TNBC cells. This method also offers a promising alternative to chimeric antigen receptor (CAR)-engineered immune cells, mitigating issues related to genetic modification, such as complex production steps and off-tumor effects. Recognizing the distinct benefits of non-genetic lipid insertion when compared to CAR-based methods, this study employed lipid-mediated cell surface engineering using lipid-PEG conjugates. Considering both the diversity of cell membrane compositions across different cell types and the amphiphilic feature of each lipid-PEG, we aimed to determine the optimal lipid anchor for effective integration into TNBC cells. In this context, 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), and cholesterol (CLS) were evaluated for their suitability in TNBC cell surface modification. Each lipid anchor demonstrated unique properties in terms of membrane insertion, stability, and biological compatibility. Notably, DMPE outperformed the other lipids, exhibiting efficient membrane coating and prolonged retention on the TNBC cell surface. These findings emphasize the significance of a multi-criteria approach for lipid selection and present a widely applicable methodology for lipid-based cancer cell surface engineering.Graphical abstractOptimal lipid selection for TNBC cell surface engineering was performed to anchor artificial receptors, aiming to enhance the recognition and targetability of TNBC cell that lacks representative surface antigens.