biostudies-literatureJiang CScience and Technology Development Fund of Shanghai Pudong New AreaNational Natural Science Foundation of ChinaShanghai Scientific and Technological Innovation Programe2102500https://www.ebi.ac.uk/biostudies/studies/S-EPMC8529437biostudies-literatureUnknown8(20)Combinations of immune checkpoint therapies show encouraging results in the treatment of many human cancers. However, the higher costs and greater side effects of such combinations compared with single-agent immunotherapies limit their further applications. In this work, a novel smart agent, KN046@¹⁹ F-ZIF-8, is developed to overcome these limitations. KN046 is a novel recombinant humanized PD-L1/CTLA-4 bispecific single-domain antibody-Fc fusion protein, which can bind to both PD-L1 and CTLA-4 effectively. ZIF-8 is a smart delivery system, which can safely and effectively deliver KN406 to a tumor. In vitro and in vivo results demonstrate that the smart agent KN046@¹⁹ F-ZIF-8 not only improves the immune response rate of the antibody drug in treatment of tumors but alAdvanced science (Weinheim, Baden-Wurttemberg, Germany)Engineering a Smart Agent for Enhanced Immunotherapy Effect by Simultaneously Blocking PD-L1 and CTLA-4.PMC852943781771861PKJ2020-Y558197164819142202100He SQi MZhang JSong SJiang CZhang LXu XTian QfalseEngineering a Smart Agent for Enhanced Immunotherapy Effect by Simultaneously Blocking PD-L1 and CTLA-4.Combinations of immune checkpoint therapies show encouraging results in the treatment of many human cancers. However, the higher costs and greater side effects of such combinations compared with single-agent immunotherapies limit their further applications. In this work, a novel smart agent, KN046@¹⁹ F-ZIF-8, is developed to overcome these limitations. KN046 is a novel recombinant humanized PD-L1/CTLA-4 bispecific single-domain antibody-Fc fusion protein, which can bind to both PD-L1 and CTLA-4 effectively. ZIF-8 is a smart delivery system, which can safely and effectively deliver KN406 to a tumor. In vitro and in vivo results demonstrate that the smart agent KN046@¹⁹ F-ZIF-8 not only improves the immune response rate of the antibody drug in treatment of tumors but al2021-01-01T00:00:00Z2021 Oct2025-05-18T12:07:13.591Z2025-05-18T12:07:13.591ZS-EPMC85294373447343010.1002/advs.202102500