Xiao Zecong, Tan Yitong, Cai Yujun, Huang Jinsheng, Wang Xiaobin, Li Bo, Lin Liteng, Wang Yong, Shuai Xintao, Zhu Kangshun
Department of Minimally Invasive Interventional Radiology, and Laboratory of Interventional Radiology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
J Control Release. 2023 Apr;356:360-372. doi: 10.1016/j.jconrel.2023.02.029. Epub 2023 Mar 10.
The dense extracellular matrix (ECM) is a key barrier to tumor infiltration of cytotoxic T lymphocytes (CTLs), which greatly compromises T cell-dependent immunotherapy of hepatocellular carcinoma (HCC). Herein, hyaluronidase (HAase), IL-12, and anti-PD-L1 antibody (αPD-L1) were co-delivered using a pH and MMP-2 dual-sensitive polymer/calcium phosphate (CaP) hybrid nanocarrier. The dissolution of CaP triggered by tumor acidity facilitated the release of IL-12 and HAase responsible for ECM digestion, enhancing the tumor infiltration and proliferation of CTLs. Furthermore, the in situ-released αPD-L1 inside tumor, as triggered by an overexpressed MMP-2, prevented the tumor cell from escaping the killing effects of CTLs. Such combination strategy induced a robust antitumor immunity for efficiently suppressing HCC growth in mice. Additionally, tumor acidity-sheddable polyethylene glycol (PEG) coating enhanced the tumor accumulation of nanocarrier and reduced the immune-related adverse events (irAEs) induced by on-target off-tumor αPD-L1. This dual-sensitive nanodrug demonstrates an effective immunotherapy paradigm for other dense ECM-characterized solid tumors.
致密的细胞外基质（ECM）是细胞毒性T淋巴细胞（CTL）浸润肿瘤的关键障碍，这极大地损害了肝细胞癌（HCC）的T细胞依赖性免疫治疗。在此，使用pH和基质金属蛋白酶-2（MMP-2）双敏感聚合物/磷酸钙（CaP）杂化纳米载体共同递送透明质酸酶（HAase）、白细胞介素-12（IL-12）和抗程序性死亡配体1抗体（αPD-L1）。肿瘤酸性触发的CaP溶解促进了负责ECM消化的IL-12和HAase的释放，增强了CTL的肿瘤浸润和增殖。此外，由过表达的MMP-2触发的肿瘤内原位释放的αPD-L1可防止肿瘤细胞逃避CTL的杀伤作用。这种联合策略诱导了强大的抗肿瘤免疫力，有效抑制了小鼠体内HCC的生长。此外，肿瘤酸性可脱落的聚乙二醇（PEG）涂层增强了纳米载体在肿瘤中的积累，并减少了由肿瘤靶向非肿瘤αPD-L1诱导的免疫相关不良事件（irAEs）。这种双敏感纳米药物为其他具有致密ECM特征的实体瘤展示了一种有效的免疫治疗模式。
