Song, Sukyung Shim, Man Kyu Yang, Suah Lee, Jaewan Yun, Wan Su Cho, Hanhee Moon, Yujeong Min, Jin Young Han, Eun Hee Yoon, Hong Yeol Kim, Kwangmeyung 2024-01-19T08:32:47Z 2024-01-19T08:32:47Z 2023-07-13 2023-10 2452-199X https://pubs.kist.re.kr/handle/201004/113244 Synergistic immunotherapy of immune checkpoint blockade (ICB) and immunogenic cell death (ICD) has shown remarkable therapeutic efficacy in various cancers. However, patients show low response rates and undesirable outcomes to these combination therapies owing to the recycling mechanism of programmed death-ligand 1 (PDL1) and the systemic toxicity of ICD-inducing chemotherapeutic drugs. Herein, we propose all-in-one glycol chitosan nanoparticles (CNPs) that can deliver anti-PD-L1 peptide (PP) and doxorubicin (DOX) to targeted tumor tissues for a safe and more effective synergistic immunotherapy. The PP-CNPs, which are prepared by conjugating ᴅ-form PP (NYSKPTDRQYHF) to CNPs, form stable nanoparticles that promote multivalent binding with PD-L1 proteins on the targeted tumor cell surface, resulting in effective lysosomal PD-L1 degradation in contrast with anti-PD-L1 antibody, which induces recycling of endocytosed PD-L1. Consequently, PP-CNPs prevent subcellular PD-L1 recycling and eventually destruct immune escape mechanism in CT26 colon tumor-bearing mice. Moreover, the ICD inducer, DOX is loaded into PP-CNPs (DOX-PP-CNPs) for synergistic ICD and ICB therapy, inducing a large number of damage-associated molecular patterns (DAMPs) in targeted tumor tissues with minimal toxicity in normal tissues. When the DOX-PP-CNPs are intravenously injected into CT26 colon tumor-bearing mice, PP and DOX are efficiently delivered to the tumor tissues via nanoparticle-derived passive and active targeting, which eventually induce both lysosomal PD-L1 degradation and substantial ICD, resulting in a high rate of complete tumor regression (CR: 60%) by a strong antitumor immune response. Collectively, this study demonstrates the superior efficacy of synergistic immunotherapy using all-in-one nanoparticles to deliver PP and DOX to targeted tumor tissues. English Elsevier All-in-one glycol chitosan nanoparticles for co-delivery of doxorubicin and anti-PD-L1 peptide in cancer immunotherapy Article 10.1016/j.bioactmat.2023.05.016 1 Bioactive Materials, v.28, pp.358 - 375 Bioactive Materials 28 358 375 Y scie scopus 001017443400001 2-s2.0-85161307297 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article DRUG-DELIVERY MULTIFUNCTIONAL NANOPARTICLES CELLULAR UPTAKE EFFICACY ANTIBODY ENHANCE STABILITY PD-L1 Chitosan nanoparticle Synergistic immunotherapy Immune checkpoint blockade Multivalent binding Immunogenic cell death