1. Academic Validation
  2. The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment

The programmed site-specific delivery of LY3200882 and PD-L1 siRNA boosts immunotherapy for triple-negative breast cancer by remodeling tumor microenvironment

  • Biomaterials. 2022 May;284:121518. doi: 10.1016/j.biomaterials.2022.121518.
Pan Zhang 1 Chao Qin 1 Nan Liu 1 Xinyuan Zhou 1 Xuxin Chu 1 Fangnan Lv 1 Yongwei Gu 2 Lifang Yin 1 Jiyong Liu 3 Jianping Zhou 4 Meirong Huo 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, NO.639 Longmian Avenue, Nanjing, 211198, China.
  • 2 Department of Pharmacy, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3 Department of Pharmacy, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: liujiyong@fudan.edu.cn.
  • 4 State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, NO.639 Longmian Avenue, Nanjing, 211198, China. Electronic address: cpu_zhoujp@163.com.
  • 5 State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, NO.639 Longmian Avenue, Nanjing, 211198, China. Electronic address: huomeirongcpu@163.com.
Abstract

Despite the remarkable success of immunotherapies over the past decade, their effectiveness against triple-negative breast Cancer (TNBC) is limited to a small subset of patients, mainly due to the low immunogenicity and unfavorable tumor microenvironment. In this study, we successfully constructed a programmed site-specific delivery nanosystem for the combined delivery of transforming growth factor beta (TGF-β) receptor inhibitor LY3200882 (LY) and PD-L1 siRNA (siPD-L1) to boost anti-tumor immunotherapy. As expected, LY in the outer layer of the nanosystem was released by stimulation of MMP2, and dramatically down-regulated the expression of extracellular matrix (ECM) in the tumor-associated fibroblasts (TAFs), and thus promoted the infiltration of effector T cells and penetration of nanomedicines. Simultaneously, the blockade of TGF-β by LY also triggered immunogenic cell death (ICD) of tumor cells and induced the maturation of dendritic cells. Moreover, the programmed design provided the siPD-L1/protamine cationic inner core with easier access to tumor cells and TAFs after MMP2-stimulated breakup of the outer layer, down-regulating the expression of PD-L1 in both types of cells. Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC.

Keywords

Immunogenic cell death; Immunosuppressive tumor microenvironment; Immunotherapy; PD-L1; TGF-β; Tumor-associated fibroblasts.

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