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Smart Nanomedicine to Enable Crossing Blood-Brain Barrier Delivery of Checkpoint Blockade Antibody for Immunotherapy of Glioma.

Immune checkpoint blockade (ICB) therapy has shown tremendous promises in the treatment of various types of tumors. However, ICB therapy with antibodies appears to be less effective for glioma, partly owing to the existence of the blood-brain barrier (BBB) that impedes the entrance of therapeutics including most proteins to the central nervous system (CNS). Herein, considering the widely existing nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) on the surface of BBB, a choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) is employed to fabricate the BBB-crossing copolymer via free-radical polymerization, followed by conjugation with antiprogrammed death-ligand 1 (anti-PD-L1) via a pH-sensitive traceless linker. The obtained nanoparticles exhibit significantly improved BBB-crossing capability owing to the receptor-mediated transportation after intravenous injection in an orthotopic glioma tumor model. Within the acidic glioma microenvironment, anti-PD-L1 would be released from such pH-responsive nanoparticles, further triggering highly effective ICB therapy of glioma to significantly prolong animal survival. This work thus realizes glioma microenvironment responsive BBB-crossing delivery of ICB antibodies, promising for the next generation immunotherapy of glioma.