Acid‐Responsive Transferrin Dissociation and GLUT Mediated Exocytosis for Increased Blood–Brain Barrier Transcytosis and Programmed Glioma Targeting Delivery

Receptor mediated transcytosis (RMT) is a common mechanism used for nanotherapeutics to traverse the blood–brain barrier (BBB). However, the transcytosis of ligand modified nanoparticles via RMT is likely to be trapped within brain capillary endothelial cells due to the high binding affinity of ligand with receptors, which greatly reduces the amount of nanoparticles across BBB. Here, P‐aminophenyl‐α‐D‐mannopyranoside (MAN) decorated doxorubicin‐loaded dendrigraft poly‐l‐lysine with acid‐cleavable transferrin (Tf) coating outside (DD‐MCT) is proposed. The DD‐MCT is engineered to specifically recognize the Tf receptor (TfR) on the luminal side of BBB endothelium. Then the DD‐MCT undergoes an acid‐responsive cleavage of Tf, leading to the separation of MAN‐decorated DGL‐DOX (DD‐M) from the Tf–TfR complex in endo/lysosomes. The detached DD‐M is more prone to escape from endo/lysosomes and can further be exocytosed into brain parenchyma via the mediation of glucose transporter located on the abluminal endothelial membrane. Moreover, the DD‐M in brain parenchyma can target glioma cells. Significantly, the DD‐MCT enters into brain parenchyma in greater amounts, resulting in enhanced accumulation at glioma site and thus improved antiglioma therapeutic outcome. This strategy pioneers a new path for reducing the trapping of nanotherapeutics within BBB endothelium but increasing their transcytosis into brain parenchyma. Acid‐cleavable transferrin and P‐aminophenyl‐α‐D‐mannopyranoside co‐modified doxorubicin‐tethered dendrigraft poly‐l‐lysine are successfully designed and synthesized. The functional nanoparticles undergo a four‐step journey within endothelial cells for programmed targeting delivery to glioma cells. The nanoparticles exhibit increased transcytosis across blood–brain barriers and precise glioma targeting effect, as well as improved chemotherapeutic outcome.