All-in-one glycol chitosan nanoparticles for co-delivery of doxorubicin and anti-PD-L1 peptide in cancer immunotherapy

• Published in: Bioactive materials 2023-10, Vol.28, p.358-375
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Chitosan nanoparticle; Immune checkpoint blockade; Immunogenic cell death; Multivalent binding; Synergistic immunotherapy
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2023.05.016

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 (PD-L1) 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. [Display omitted] •In this study, we propose a new all-in-one nanoparticle system for synergistic immunotherapy to combine PD-L1 degradation and ICD.•DOX-PP-CNPs efficiently accumulate within the tumor tissues, promoting multivalent binding with the PD-L1 on surface of tumor cells.•Multivalent binding of DOX-PP-CNPs with PD-L1 on tumor cell surface induce the lysosomal PD-L1 degradation to inhibit PD-L1 recycling.•DOX-PP-CNPs release the DOX to induce a large amount of DAMPs in tumor cells by a potent ICD for DC maturation and T cell activation.•The synergistic effect of multivalent binding-mediated PD-L1 degradation and ICD a