GE11-modified carboxymethyl chitosan micelles to deliver DOX·PD-L1 siRNA complex for combination of ICD and immune escape inhibition against tumor

• Published in: Carbohydrate polymers 2023-07, Vol.312, p.120837-120837, Article 120837
• Main Authors: Song, Panpan, Wang, Bingjie, Pan, Qi, Jiang, Tianze, Chen, Xiangyan, Zhang, Miao, Tao, Jiaojiao, Zhao, Xia
• Format: Article
• Language: English
• Subjects: Carboxymethyl chitosan; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chitosan; Doxorubicin; Doxorubicin - pharmacology; Immunogenic Cell Death; Micelles; PD-L1 siRNA; RNA, Small Interfering
• ISSN: 0144-8617; 1879-1344
• DOI: 10.1016/j.carbpol.2023.120837

Programmed cell death-ligand 1 (PD-L1) small interfering RNA (siRNA) achieves tumor immunotherapy by restoring the immune response of T cells, but the efficacy of PD-1/PD-L1 monotherapy is relatively low. While immunogenic cell death (ICD) can improve the response of most tumors to anti-PD-L1 and enhance tumor immunotherapy. Herein, a targeting peptide GE11-functionalized dual-responsive carboxymethyl chitosan (CMCS) micelle (G-CMssOA) is developed for simultaneous delivery of PD-L1 siRNA and doxorubicin (DOX) in a complex form of DOX·PD-L1 siRNA (D&P). The complex-loaded micelles (G-CMssOA/D&P) have good physiological stability and pH/reduction responsiveness, and improve the intratumoral infiltration of CD4+ and CD8+ T cells, reduce Tregs (TGF-β), and increase the secretion of immune-stimulatory cytokine (TNF-α). The combination of DOX-induced ICD and PD-L1 siRNA-mediated immune escape inhibition significantly improves anti-tumor immune response and inhibits tumor growth. This complex delivery strategy provides a new approach for effectively delivering siRNA and enhancing anti-tumor immunotherapy. [Display omitted]