Engineered tantalum sulfide nanosheets for effective acute liver injury treatment by regulating oxidative stress and inflammation

Abstract

Introduction

Tantalum sulfide (TaS₂), a two-dimensional layered material, shows significant promise for treating acute liver injury (ALI) due to its exceptional biocompatibility and potent reactive oxygen species (ROS) scavenging capacity. However, the clinical translation of TaS₂-based therapy remains limited by challenges in optimizing its stability, bioavailability, and particle size to match the liver’s complex architecture.

Objectives

This study investigated the mechanisms by which serum albumin (SA)-modified TaS₂ nanosheets (S-TaS₂) modulate oxidative stress, apoptosis, and inflammation to achieve therapeutic efficacy in ALI.

Methods

S-TaS₂ was synthesized via a top-down exfoliation strategy and comprehensively characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), ultraviolet–visible (UV–Vis) spectroscopy, and Zeta potential analysis. In vivo therapeutic performance was evaluated through liver function tests, Hematoxylin-Eosin staining (HE), Dihydroethidium (DHE) staining, 8-Hydroxy-2′-deoxyguanosine (8-OHdG) staining, and ROS level assessments. Biodistribution, mitochondrial protection, and anti-inflammatory effects of S-TaS₂ were assessed via in vivo fluorescence imaging, immunohistochemistry, western blotting, JC-1 and Mitochondrial Superoxide (MitoSOX) staining, Annexin V-fluorescein isothiocyanate (FITC)/Propidium Iodide (PI) apoptosis assays, enzyme-linked immunosorbent assays (ELISA), and other complementary techniques.

Results

The exfoliation process successfully reduced TaS₂ to monolayer nanosheets, yielding a nanoscale formulation with improved bioactivity. SA modification significantly enhanced aqueous stability and enabled targeted liver delivery. This targeting effect is attributed to two factors: the inherent liver affinity of SA and the optimal particle size of S-TaS₂ (∼185 nm), which facilitates passage through hepatic sinusoids (50–200 nm) and, in pathological conditions such as ALI, through damaged vascular endothelium. In an acetaminophen (APAP)-induced ALI model, S-TaS₂ preferentially accumulated in the injured liver, where it scavenged excessive ROS, mitigated mitochondrial dysfunction, and significantly preserved hepatocyte integrity. Notably, S-TaS₂ also attenuated liver inflammation, reduced pro-inflammatory cytokine levels, and promoted tissue repair. Furthermore, it demonstrated adequate biosafety both in vitro and in vivo.

Conclusions

This study presents the first successful synthesis of S-TaS₂, a liver-targeting nanotherapeutic engineered through SA modification and size optimization. S-TaS₂ preferentially accumulates in damaged hepatic tissue and effectively combats ALI by suppressing oxidative stress and inflammation, while preventing their pathological amplification. These findings offer new therapeutic insights and a promising platform for future liver-targeted interventions.