Promoting transcellular traversal of the blood–brain barrier by simultaneously improving cellular uptake and accelerating lysosomal escape†

The blood–brain barrier (BBB) impedes the transportation of drugs to the brain, thereby constraining the efficacy of treatments for brain diseases. Here, a pH-sensitive nanocarrier coated with a brain metastatic tumor cell membrane (CA-iRGD-CS@M) is designed to enhance drug delivery across the BBB by simultaneously improving cellular uptake and accelerating lysosomal escape. The cell membrane coating can recognize brain microvessel endothelial cells (BMECs) to improve cellular uptake. The pH-sensitive nanocarrier (CA-iRGD-CS) as the core of CA-iRGD-CS@M undergoes charge reversal triggered by the acidic environment of lysosomes, leading to the disruption of the coated cell membrane and further promoting the escape of the detached core from lysosomes into the brain parenchyma. Facilitated by the targeting ligand iRGD, the detached core containing the photothermal agent (CuS) can target the tumor site and fulfill deep penetration, thereby achieving efficient NIR-II photothermal therapy.