基于磁性金属有机框架并包覆血小板膜的纳米平台作为协同程序性细胞死亡蛋白 1 抑制剂用于肝细胞癌治疗

Programmed cell death protein 1 (PD-1) inhibitors are the most common immune-checkpoint inhibitors and considered promising drugs for hepatocellular carcinoma (HCC).

However, in clinical settings, they have a low objective response rate (15%-20%) for patients with HCC; this is because of the insufficient level and activity of tumor-infiltrating T lymphocytes (TILs). The combined administration of oxymatrine (Om) and astragaloside IV (As) can increase the levels of TILs by inhibiting the activation of cancer-associated fibroblasts (CAFs) and improve the activity of TILs by enhancing their mitochondrial function.

In the present study, we constructed a magnetic metal-organic framework (MOF)-based nanoplatform with platelet membrane (Pm) coating (PmMN@Om&As) to simultaneously deliver Om and As into the HCC microenvironment.

We observed that PmMN@Om&As exhibited a high total drug-loading capacity (33. 77 wt %) and good immune escape.

Furthermore, it can target HCC tissues in a magnetic field and exert long-lasting effects. The HCC microenvironment accelerated the disintegration of PmMN@Om&As and the release of Om&As, thereby increasing the level and activity of TILs by regulating CAFs and the mitochondrial function of TILs.

In addition, the carrier could synergize with Om&As by enhancing the oxygen consumption rate and proton efflux rate of TILs, thereby upregulating the mitochondrial function of TILs. Combination therapy with PmMN@Om&As and α-PD-1 resulted in a tumor suppression rate of 84. 15% and prolonged the survival time of mice.

Our study provides a promising approach to improving the antitumor effect of immunotherapy in HCC.