Carcinoma–Astrocyte\nGap Junction Interruption\nby a Dual-Targeted Biomimetic Liposomal System to Attenuate Chemoresistance\nand Treat Brain Metastasis

Brain metastasis contributes substantially to the morbidity\nand\nmortality of various malignancies and is characterized by high chemoresistance.\nIntracellular communication between carcinoma cells and astrocytes\nthrough gap junctions, which are assembled mainly by the connexin\n43 protein, has been shown to play a vital role in this process. However,\neffectively blocking the gap junctions between the two cell types\nremains extremely challenging because of insufficient drug delivery\nto the target site. Herein, we designed a connexin blocker-carbenoxolone\n(CBX)-loaded biomimetic liposomal system with artificial liposomes\nfused with brain metastatic cell and reactive astrocyte membranes\n(LAsomes) to block gap junctions and attenuate chemoresistance. LAsomes\neffectively penetrated the blood–brain barrier via semaphorin\n4D (SEMA 4D)Plexin B1 interactions and actively migrated to\ntheir source cells via homotypic recognition. Consequently, LAsomes\neffectively inhibited material transfer and Ca<sup>2+</sup> flow from\nmetastatic cells to astrocytes via gap junctions, thereby markedly\nincreasing the sensitivity of metastatic tumor cells to chemotherapy.\nThese results reveal that closing the gap junctions may be a promising\ntherapeutic strategy for intractable brain metastasis.