Rational development of molecularly imprinted nanoparticles for blocking PD-1/PD-L1 axis

Blocking the PD-1/PD-L1 immune checkpoint has emerged as a promising strategy in cancer immunotherapy, in which monoclonal antibodies are predominately used as inhibitors. Despite their remarkable success, monoclonal antibody-based therapeutics suffer from drawbacks due to the use of antibodies, such as high cost, low stability and high frequency of immune-related adverse effects. Therefore, novel anti-PD-1/PD-L1 therapeutics that can address these issues are of significant importance. Herein, we report a molecularly imprinted polymer (MIP) based PD-1 nano inhibitor for blocking the PD-1/PD-L1 axis. The anti-PD-1 nanoMIP was rationally designed and engineered by epitope imprinting using the N-terminal epitope of PD-1 as the binding site. The anti-PD-1 nanoMIP showed good specificity and high affinity towards PD-1, yielding a disassociation constant at the 10-8 M level, much better than that between PD-1 and PD-L1. Via steric hindrance, this inhibitor could effectively block PD-1/PD-L1 interaction. Besides, it could effectively reactivate T cells and reverse the chemoresistance of tumor cells. Therefore, this present study not only provides a novel and promising immune checkpoint blockade inhibitor but also boosts further development of MIPs for cancer immunotherapy.