A redox homeostasis disruptor based on a biodegradable nanoplatform for ultrasound (US) imaging-guided high-performance ferroptosis therapy of tumors.

ABSTRACT

The synergistic disruption of intracellular redox homeostasis through the combination of ferroptosis/gas therapy shows promise in enhancing the antitumor efficacy. However, the development of an optimal delivery system encounters significant challenges, including effective storage, precise delivery, and controlled release of therapeutic gas. In this study, we propose the utilization of a redox homeostasis disruptor that is selectively activated by the tumor microenvironment (TME), in conjunction with our newly developed nanoplatforms (MC@HMOS@Au@RGD), for highly efficient ferroptosis therapy of tumors. The TME-triggered degradation of HMOS initiates the release of MC and AuNPs from the MC@HMOS@Au@RGD nanoplatform. The released MC subsequently reacts with endogenous hydrogen peroxide (H2O2) and H+ to enable the on-demand release of CO gas, leading to mitochondrial damage. Simultaneously, the released AuNPs exhibit GOx-like activity, catalyzing glucose to generate gluconic acid and H2O2. This process not only promotes the decomposition of MnCO to enhance CO production but also enhances the Fenton-like reaction between Mn2+ and H2O2, generating ROS through the modulation of the H+ and H2O2-enriched TME. Moreover, the generation of CO bubbles enables the monitoring of the ferroptosis treatment process through ultrasound (US) imaging. The efficacy of our prepared MC@HMOS@Au@RGD disruptors in ferroptosis therapy is validated through both in vitro and in vivo experiments.

A strategy of disrupted redox homeostasis specifically initiated by the tumor microenvironment and our constructed MC@HMOS@Au@RGD nanoplatforms is proposed for ultrasound (US) imaging-guided potent ferroptosis therapy of tumors.