Lin Minzhao, Cai Yujun, Chen Gengjia, Zhong Huihai, Li Bo, Li Tan, Xiao Zecong, Shuai Xintao
PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
Biomaterials. 2023 May;296:122067. doi: 10.1016/j.biomaterials.2023.122067. Epub 2023 Feb 21.
Triple negative breast cancer (TNBC) as a highly aggressive and metastatic malignancy lacks targeting therapies nowadays. Moreover, although immune checkpoint blockade (ICB) is known to trigger anti-tumor immune response, most TNBC falls into the immunologically "cold" category unsuitable for ICB therapy due to insufficient lymphocyte infiltration. Herein, we develop a hierarchical targeting strategy for preparing a core-shell-structural nanodrug to concurrently block the programmed death ligand 1 (PD-L1) and deliver a stimulator of interferon gene (STING) agonist into tumor-infiltrating antigen-presenting cells (APCs). The nanodrug complexed the interferon stimulatory DNA (ISD) for STING activation in its core, conjugated PD-L1 antibody (aPD-L1) on its shell through a matrix metalloproteinase-2 (MMP-2) substrate peptide, and incorporated "hidden" mannose in its sublayer. Through aPD-L1-mediated active targeting of tumor cells and tumor-infiltrating APCs, the nanodrug efficiently accumulated in tumor sites. Then, the PD-L1-conjugating peptide was cleaved by tumor-enriched MMP-2, leaving aPD-L1 on target cells for ICB while exposing mannose to mediate targeted delivery of ISD into tumor-infiltrating dendritic cells (DCs) and tumor-associated macrophages (TAMs). Activating the STING signaling in DCs and TAMs not only stimulated the APCs maturation to prime anti-tumor immunity but also induced their chemokine secretion to promote tumor infiltration of anti-tumor effector T cells, thus sensitizing TNBC to the ICB therapy. Consequently, a potent antitumor immunity was evoked to effectively inhibit the tumor growth and metastasis in mice bearing orthotopic 4T1 breast cancer, showing the great potential in treating immunologically "cold" tumors.
三阴性乳腺癌（TNBC）作为一种具有高度侵袭性和转移性的恶性肿瘤，目前缺乏靶向治疗方法。此外，尽管免疫检查点阻断（ICB）已知可触发抗肿瘤免疫反应，但由于淋巴细胞浸润不足，大多数TNBC属于免疫“冷”型，不适合ICB治疗。在此，我们开发了一种分级靶向策略，用于制备一种核壳结构的纳米药物，以同时阻断程序性死亡配体1（PD-L1），并将干扰素基因刺激剂（STING）激动剂递送至肿瘤浸润的抗原呈递细胞（APC）中。该纳米药物在其核心中复合了用于激活STING的干扰素刺激DNA（ISD），通过基质金属蛋白酶-2（MMP-2）底物肽在其外壳上偶联了PD-L1抗体（aPD-L1），并在其亚层中掺入了“隐藏”的甘露糖。通过aPD-L1介导的对肿瘤细胞和肿瘤浸润APC的主动靶向，该纳米药物有效地在肿瘤部位积聚。然后，PD-L1偶联肽被肿瘤富集的MMP-2切割，在靶细胞上留下aPD-L1用于ICB，同时暴露甘露糖以介导ISD靶向递送至肿瘤浸润的树突状细胞（DC）和肿瘤相关巨噬细胞（TAM）。激活DC和TAM中的STING信号不仅刺激APC成熟以启动抗肿瘤免疫，还诱导它们分泌趋化因子以促进抗肿瘤效应T细胞的肿瘤浸润，从而使TNBC对ICB治疗敏感。因此，在原位接种4T1乳腺癌的小鼠中引发了强大的抗肿瘤免疫，有效抑制了肿瘤生长和转移，显示出在治疗免疫“冷”肿瘤方面的巨大潜力。
