Carcinoma–Astrocyte Gap Junction Interruption by a Dual-Targeted Biomimetic Liposomal System to Attenuate Chemoresistance and Treat Brain Metastasis

Brain metastasis contributes substantially to the morbidity and mortality of various malignancies and is characterized by high chemoresistance. Intracellular communication between carcinoma cells and astrocytes through gap junctions, which are assembled mainly by the connexin 43 protein, has been shown to play a vital role in this process. However, effectively blocking the gap junctions between the two cell types remains extremely challenging because of insufficient drug delivery to the target site. Herein, we designed a connexin blocker-carbenoxolone (CBX)-loaded biomimetic liposomal system with artificial liposomes fused with brain metastatic cell and reactive astrocyte membranes (LAsomes) to block gap junctions and attenuate chemoresistance. LAsomes effectively penetrated the blood-brain barrier via semaphorin 4D (SEMA 4D)─Plexin B1 interactions and actively migrated to their source cells via homotypic recognition. Consequently, LAsomes effectively inhibited material transfer and Ca²⁺ flow from metastatic cells to astrocytes via gap junctions, thereby markedly increasing the sensitivity of metastatic tumor cells to chemotherapy. These results reveal that closing the gap junctions may be a promising therapeutic strategy for intractable brain metastasis.