Promoting Drug Delivery to the Brain by Modulating the Transcytosis Process across the Blood–Brain Barrier

The blood-brain barrier (BBB) presents a major challenge in the theranostics of brain diseases by impeding the delivery of drugs to the brain. Currently the most common strategy for transferring substances across the BBB is receptor-mediated transcytosis, which is restricted by several key factors, including insufficient endocytosis by brain microvessel endothelial cells (BMECs) due to underexpressed pinocytotic vesicles, lysosomal retention, and limited exocytosis to the brain parenchyma. We report a hybrid cell membrane (HCM)-coated and 2-methacryloyloxyethyl phosphorylcholine (MPC)-modified nanocarrier to promote drug delivery across the BBB by modulating the transcytosis process. The HCM incorporates a brain metastatic tumor cell membrane for recognition of BMECs and a GFP-293-S cell membrane expressing Spike protein to facilitate membrane fusion between the nanocarrier and BMECs, thereby bypassing vesicle-dependent endocytosis and enhancing cellular uptake. Membrane fusion reduces the chance of lysosomal retention, and MPC modification enhances exocytosis into the brain parenchyma via the interaction of MPC with transporters expressed on the abluminal endothelial membrane. The nanocarrier achieves significantly improved delivery of CuS, a photothermal agent, to the brain and thus enables highly efficient therapy of brain glioma.