通过肽模拟 LNP 介导的 RNAi 系统递送沉默 STAT3 下调 PD-L1 并抑制黑色素瘤生长。

Silencing of STAT3 via Peptidomimetic LNP-Mediated Systemic Delivery of RNAi Downregulates PD-L1 and Inhibits Melanoma Growth.

机构信息

Institute of Mongolian Medicinal Chemistry, School of Chemistry & Chemical Engineering, Inner Mongolia University, Hohhot 010020, Inner Mongolia, China.

出版信息

Biomolecules. 2020 Feb 12;10(2):285. doi: 10.3390/biom10020285.

Cutaneous melanoma is the most aggressive skin cancer with notorious drug resistance. Inhibition of immune checkpoint molecules is one of the most promising approaches for cancer therapy. Herein, we show that RNAi mediated silencing of STAT3 expression in the tumor tissue robustly inhibit tumor growth in B16F10 mouse model of melanoma. We designed a peptidomimetic-based lipid nanoparticles (LNPs) for the delivery of siRNA in mouse model of melanoma. When systemically administered, the novel formulation (denote DoCh) preferentially delivered siRNA to the tumor tissue. Remarkably, sequential intravenous injections of siRNA against STAT3 induced profound silencing of STAT3 expression in tumor tissue, which resulted in significant downregulation of PD-L1, leading to significant inhibition of tumor growth through inhibition of tumor immune checkpoint. Moreover, DoCh-mediated siRNA delivery did not show noticeable damage to the major organs. Collectively, our data demonstrated that DoCh LNP is a promising tumor-targeted siRNA delivery system.

皮肤黑色素瘤是最具侵袭性的皮肤癌，其耐药性臭名昭著。抑制免疫检查点分子是癌症治疗最有前途的方法之一。在此，我们表明，在黑色素瘤的 B16F10 小鼠模型中，通过 RNAi 介导的 STAT3 表达沉默可强烈抑制肿瘤生长。我们设计了一种基于肽模拟的脂质纳米颗粒（LNPs）用于在黑色素瘤小鼠模型中递送 siRNA。当系统给药时，新型制剂（表示为 DoCh）优先将 siRNA 递送到肿瘤组织。值得注意的是，连续静脉注射针对 STAT3 的 siRNA 可在肿瘤组织中诱导 STAT3 表达的显著沉默，从而导致 PD-L1 的显著下调，通过抑制肿瘤免疫检查点导致肿瘤生长的显著抑制。此外，DoCh 介导的 siRNA 递送不会对主要器官造成明显损伤。总之，我们的数据表明，DoCh LNP 是一种有前途的肿瘤靶向 siRNA 递送系统。