Selective vascular disrupting therapy by lipid nanoparticle-mediated Fas ligand silencing and stimulation of STING

Abstract

Although recent therapeutic developments have greatly improved the outcomes of patients with cancer, it remains on ongoing problem, particularly in relation to acquired drug resistance. Vascular disrupting agents (VDAs) directly damage tumor blood vessels, thus promoting drug efficacy and reducing the development of drug resistance; however, their low molecular weight and resulting lack of selectivity for tumor endothelial cells (TECs) lead to side effects that can hinder their practical use. Here, we report a novel tumor vascular disrupting therapy using nucleic acid-loaded lipid nanoparticles (LNPs). We prepared two LNPs: a small interfering RNA (siRNA) against Fas ligand (FasL)-loaded cyclic RGD modified LNP (cRGD-LNP) to knock down FasL in TECs and a stimulator of interferon genes (STING) agonist-loaded LNP to induce systemic type I interferon (IFN) production. The combination therapy disrupted the tumor vasculature and induced broad tumor cell apoptosis within 48 h, leading to rapid and strong therapeutic effects in various tumor models. T cells were not involved in these antitumor effects. Furthermore, the combination therapy demonstrated a significantly superior therapeutic efficacy compared with conventional anti-angiogenic agents and VDAs. RNA sequencing analysis suggested that reduced collagen levels may have been responsible for TEC apoptosis. These findings demonstrated a potential therapeutic method for targeting the tumor vasculature, which may contribute to the development of a new class of anti-cancer drugs.

Keywords: Cancer therapy; FasL; Lipid nanoparticle; Nanomedicine; STING; Tumor vascular disrupting therapy.