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

Abstract

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.

Salviolone from Salvia miltiorrhiza Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation

“…The transcription factor STAT3 has a key role in the onset and progression of cancer. Actually, in a mouse model, the silencing of STAT3 expression results in melanoma growth inhibition [44]. Certainly, the activation of STAT3 elicits the expression of many target genes that are involved in cell proliferation, apoptosis, metastasis, inflammation, immunity, and angiogenesis [45].…”

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections

“…Recently, we registered, in the two human melanoma A375 and MeWo cell lines, that ONC decreases the expression level of the antiapoptotic protein Bcl2 and of the total content of the signal transducer and activator of transcription (STAT)3, together with its active forms and its upstream kinase Src [ 137 ]. Notably, STAT3 silencing strongly inhibits the tumor growth in a mouse melanoma model [ 154 ]. Hence, the ONC-related downregulation of both STAT3 and Bcl2 can partially explain either the apoptosis induction or the reduction in colony formation found in soft agar with these two melanoma cell lines [ 137 ].…”

Progress in Natural Compounds/siRNA Co-delivery Employing Nanovehicles for Cancer Therapy

“…RNA interference (RNAi) is one of the most powerful genetic tools used in anticancer therapy . Cancer occurs as a result of mutations in onco-suppressor and oncogene factors, leading to uncontrolled cell growth and inhibition of apoptosis. , Different driver genes accounting for enhancing growth and malignancy of cancer have been identified . RNA interference is beneficial in the modulation of the aforementioned genes in anticancer therapy. , The discovery of RNAi and its application have a long history; RNAi was first discovered in plants.…”

“…64,65 Different driver genes accounting for enhancing growth and malignancy of cancer have been identified. 66 RNA interference is beneficial in the modulation of the aforementioned genes in anticancer therapy. 67,68 The discovery of RNAi and its application have a long history; RNAi was first discovered in plants.…”