Nanoparticle-Based MRI-Guided Tumor Microenvironment Heating via the Synergistic Effect of Ferroptosis and Inhibition of TGF-β Signaling.

Abstract

Although induction of ferroptosis and inhibition of transforming growth factor-β (TGF-β) signaling are both effective ways to reform the tumor microenvironment (TME) and render low-immunogenic tumors responsive to immune checkpoint inhibitor (ICI) therapy, dose-limiting side effects remain major obstacles hindering their clinical application. Herein, a novel sorafenib and anti-TGF-β antibody loaded Fe3 O4 /Gd2 O3 hybrid nanoparticles with conjugation of RGD dimer (FeGd-HN@Sorafenib@TGF-β-antibody@RGD2, FG-STR) is developed. Sorafenib significantly enhances FeGd-HN-triggered ferroptosis and improves maturation and phagocytosis of dendritic cells (DCs) by inducing damage-associated molecular patterns released from ferroptotic cancer cells, while the anti-TGF-β antibody further synergizes with enhanced ferroptosis to promote DC maturation and the recruitment of CD8+ T cells, thus heating the TME. Moreover, incorporation of RGD2 facilitates uptake of the FG-STR in tumor cells which led to a significant dosage reduction of both sorafenib and anti-TGF-β antibody to avoid dose-limiting toxicities. Finally, in vitro and in vivo experiments shows that FG-STR has significantly superior intrinsic magnetic resonance imaging (MRI) capability than that of Gadovist, effectively inhibits tumor growth and lung metastasis, and increased the efficacy of anti-programmed cell death-1 treatment. Taken together, this study provides a promising strategy for new advanced MRI-guided TME heating therapies. This article is protected by copyright. All rights reserved.