Nanoparticle‐Based MRI‐Guided Tumor Microenvironment Heating via the Synergistic Effect of Ferroptosis and Inhibition of TGF‐<i>β</i> 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 therapy, dose-limiting side effects remain major obstacles hindering their clinical application. Herein, novel sorafenib and anti-TGF-β antibody loaded Fe₃ O₄ /Gd₂ O₃ hybrid nanoparticles with conjugation of arginine-glycine-aspartic dimer (FeGd-HN@Sorafenib@TGF-β-antibody@RGD2, FG-STR) are 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, the incorporation of RGD2 facilitates the uptake of the FG-STR in tumor cells which lead 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 show that FG-STR has significantly superior intrinsic magnetic resonance imaging (MRI) capability than that of Gadovist, effectively inhibits tumor growth and lung metastasis, and increases 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.