The blood-brain barrier (BBB) is a highly selective and dynamic interface separating the central nervous system from the systemic circulation, consisting of tightly interconnected endothelial cells (ECs) lining the capillaries of the brain, pericytes and astrocytes. Its limited permeability poses a major challenge for therapeutic delivery to the brain. Nanoparticles (NPs) are eligible for brain drug delivery, offering advantages in crossing biological barriers due to their versatility in synthesis, surface tailoring, shape, size and deformability. Despite these attributes, innovative design strategies are required for an efficient BBB crossing. Brain metastatic cells (BMCs) have a remarkable ability to cross the BBB and form secondary tumors in the brain, thanks to specific proteins and lipid structures on their plasma membrane (PM) that interact with BBB ECs to mediate translocation. By mimicking their natural strategies for BBB traversal, this study aims to design metastatic-derived hybrid liposomes (MDHL) obtained from synthetic lipids and PM fragments from BMCs, endowing NPs with the cell’s unique protein and lipid signatures. Firstly, an efficient PM extraction protocol was validated with Western blot analysis. MDHL were prepared by a mechanically tuned assembly procedure. FRET assay and Raman spectroscopy confirmed the hybridization of PM with synthetic lipids, and DLS techniques showed an average dimension of less than 140 nm, stable for at least 20 days. Cell viability assay confirmed their non-toxic nature on human ECs and a BBB Transwell® in vitro model was used to assess their BBB permeability. Indeed, nanoparticle tracking analysis quantified BBB crossing efficiency, showing promising potential for MDHL as an effective drug delivery nanosystems. Future work aims to use PM from different BMCs lines to identify, by proteomic and lipidomic analysis, the fingerprint of proteins and lipids responsible for enhanced BBB penetration and efficient drug delivery.
Patrucco et al. (Wed,) studied this question.