Reactive oxygen species (ROS) are reactive molecules that contain oxygen or oxygen-derived radicals, such as singlet oxygen (1O2), hydrogen peroxide (H2O2), hydroxyl radical (•OH), and superoxide anion (O2•−). They can induce oxidative stress at high concentrations, leading to diseases like cancer and inflammation. Tumor cells, characterized by higher ROS levels due to rapid energy metabolism, mitochondrial dysfunction, and lower pH, are particularly vulnerable. [1], [2] Mitochondria, being both the primary source and target of ROS, are crucial for both cell survival and death. Targeting mitochondria with drugs like alpha-tocopheryl succinate (α-TOS) that modulate ROS production and induce apoptosis has emerged as a promising cancer therapy strategy. [3], [4] Alpha-tocopheryl succinate (α-TOS) is a derivative of alpha-tocopherol that has an ester bond with succinic acid. Unlike alpha-tocopherol, which is an antioxidant, α-TOS is a mitochondrial-targeted drug that has pro-oxidant and pro-apoptotic effects. It can increase ROS and trigger apoptosis by impairing mitochondrial function and causing oxidative damage. [5], [6] However, α-TOS's limited water solubility and cellular uptake restrict its effectiveness. [7] To overcome this, strategies like photodynamic and chemodynamic therapy (CDT) have been developed to enhance ROS generation in tumor cells. CDT employs the Fenton reaction to generate toxic hydroxyl radicals from hydrogen peroxide and iron ions, leading to lipid peroxidation and ferroptosis, a new regulated cell death form. [8], [9] Nevertheless, CDT faces challenges including antioxidant enzyme expression,[10] deficiencies in iron or hydrogen peroxide, and maintaining redox balance in tumor cells. [11], [12]

Polymers, widely used as drug carriers, can deliver anticancer agents or metal ions to tumors. [13], [14] Tumor microenvironment-specific responsive polymer drug delivery systems enable rapid, selective drug release within tumors, increasing therapeutic efficacy while reducing side effects. [15] For example, polyamino acids with imidazole groups can bind substantial amounts of metal ions (e.g., iron) for CDT. These groups undergo protonation and electrostatic repulsion in acidic tumor environments, triggering pH-responsive nanoparticle disassembly and metal ion release. [16] We hypothesized that an iron-based polymer nanoparticle system that concurrently achieves ROS self-supply and glutathione (GSH) depletion would effectively supply Fenton reaction substrates, generate hydroxyl radicals, disrupt redox balance, and induce ferroptosis in tumor cells. [17], [18]

Consequently, we synthesized acid-responsive polyethylene glycol-b-polyamino acid block copolymers (PPA) with Fe3+ and α-TOS (PPA/TF). These target mitochondria to produce ROS for the Fenton reaction, in which Fe3+ is reduced to Fe2+ by GSH, and then Fe2+ generates hydroxyl radicals, causing oxidative damage and ferroptosis. At neutral pH, PPA/TF micelles maintain a stable core-shell structure, enhancing tumor accumulation through the enhanced permeability and retention (EPR) effect. [19] Once internalized by cancer cells, the protonated imidazole groups on the PPA segment lead to micelle disintegration and iron and α-TOS release. This interaction with mitochondria boosts ROS production and depletes GSH, producing hydroxyl radicals. Overall, our PPA/TF micelles offer prolonged in vivo circulation and tumor-specific drug release. By combining mitochondrial α-TOS and iron ions, this nanotherapy presents a synergistic approach to disrupt tumor cell redox balance, inducing both apoptotic and ferroptotic cell death. Scheme 1