Redox-driven hybrid nanoenzyme dynamically activating ferroptosis and disulfidptosis for hepatocellular carcinoma theranostics

Abstract

Hepatocellular carcinoma (HCC) presents formidable therapeutic challenges due to its pronounced metabolic heterogeneity, particularly arising from spatially uneven glucose availability within the tumor microenvironment (TME). To address this, we developed a glutathione (GSH)-responsive, biomimetic hybrid nanoenzyme system (M@GOx/Fe-HMON) composed of hollow mesoporous organosilica nanoparticles co-loaded with glucose oxidase (GOx) and Fe²⁺/Fe³⁺ redox pairs, and cloaked in homologous tumor cell membranes for enhanced targeting. In glucose-rich regions, the nanoenzyme orchestrates a GOx-peroxidase (POD) cascade that produces reactive oxygen species (ROS) via the Fenton reaction, leading to ferroptosis through intensified oxidative stress and GSH depletion. Conversely, under glucose-deficient conditions, the nanoenzyme promotes disulfidptosis by aggravating glucose deprivation, depleting nicotinamide adenine dinucleotide phosphate (NADPH), and impairing cystine metabolism, ultimately resulting in actin cytoskeletal collapse. This dual-action platform dynamically adapts to the tumor's metabolic landscape, selectively inducing ferroptosis or disulfidptosis according to glucose levels, disrupting redox homeostasis and amplifying antitumor efficacy. Notably, this study is the first to integrate ferroptosis and disulfidptosis activation into a single, metabolism-sensitive nanoenzyme system, providing a novel paradigm for exploiting tumor metabolic heterogeneity. Furthermore, the combination of endogenous metabolic regulation with magnetic resonance imaging (MRI)-guided diagnosis introduces an innovative and noninvasive strategy for precision cancer theranostics.

Keywords: Disulfidptosis; Ferroptosis; Magnetic resonance imaging; Metabolic heterogeneity; Tumor therapy.