Designing a Sulfur Vacancy Redox Disruptor for Photothermoelectric and Cascade-Catalytic-Driven Cuproptosis–Ferroptosis–Apoptosis Therapy

Abstract

The therapeutic efficacy of cuproptosis, ferroptosis, and apoptosis is hindered by inadequate intracellular copper and iron levels, hypoxia, and elevated glutathione (GSH) expression in tumor cells. Thermoelectric technology is an emerging frontier in medical therapy that aims to achieve efficient thermal and electrical transport characteristics within a narrow thermal range for biological systems. Here, we systematically constructed biodegradable Cu2MnS3-x-PEG/glucose oxidase (MCPG) with sulfur vacancies (SV) using photothermoelectric catalysis (PTEC), photothermal-enhanced enzyme catalysis, and starvation therapy. This triggers GSH consumption and disrupts intracellular redox homeostasis, leading to immunogenic cell death. Under 1064 nm laser irradiation, MCPG enriched with SV, owing to doping, generates a local temperature gradient that activates PTEC and produces toxic reactive oxygen species (ROS). Hydroxyl radicals and oxygen are generated through peroxide and catalase-like processes. Increased oxygen levels alleviate tumor hypoxia, whereas hydrogen peroxide production from glycometabolism provides sufficient ROS for a cascade catalytic reaction, establishing a self-reinforcing positive mechanism. Density functional theory calculations demonstrated that vacancy defects effectively enhanced enzyme catalytic activity. Multimodal imaging-guided synergistic therapy not only damages tumor cells, but also elicits an antitumor immune response to inhibit tumor metastasis. This study offers novel insights into the cuproptosis/ferroptosis/apoptosis pathways of Cu-based PTEC nanozymes.

1. Introduction

Cancer is a considerable challenge that necessitates the development of innovative therapeutic strategies. Thermoelectric catalytic therapy (TECT) is an emerging therapeutic modality that converts thermal energy into electrical electricity via a temperature gradient, separating electron–hole (e−–h+) pairs and generating an intrinsic electric field [1, 2]. This process triggers redox reactions and reactive oxygen species (ROS) production, subsequently triggering tumor cell apoptosis [3]. However, TECT efficacy is constrained by the limited temperature variation within the organism.

Driven by the photothermoelectric (PTE) effect, using heat as an energy input demonstrates enhanced efficiency in light–thermal–electric energy conversion. Notably, PTE catalysis (PTEC) is an emerging intelligent strategy. When a PTE material is exposed to laser, a regional temperature elevation occurs because of its photothermal performance. This subsequently creates a temperature gradient, leading to the movement of charge carriers from the hotter to cooler regions and establishing a potential difference, which is known as the Seebeck effect [4–7]. In particular, TECT and PTEC exhibit distinct differences in mechanisms and energy source. TECT uses thermal energy and electrical energy as the primary driving forces, induces localized thermal effects via temperature gradients, and integrates the electric field regulation to catalyze reactions. Specifically, thermal energy facilitates the adsorption and dissociation processes on the catalyst surface, whereas electrical energy enhances the efficiency of redox reactions. In contrast, PTEC integrates light energy, thermal energy, and electrical energy into a unified system. Light energy serves as the excitation source and generates e−–h+ pairs via photocatalysts to par...