Endoplasmic reticulum-targeting prodrug nanoassemblies for potent ferroptosis therapy via concurrent glutathione depletion and arachidonic acid accumulation

Ferroptosis has emerged as a promising strategy for cancer treatment, which damages tumor cells by triggering the lethal accumulation of reactive oxygen species (ROS) and lipid peroxides. However, the development of efficient ferroptosis-inducing medicines is severely impeded by the unidentified key subcellular sites of lipid peroxidation. Given the critical role of endoplasmic reticulum (ER) during ferroptosis, an ER-targeting prodrug nanoassembly (ISSM) is designed to efficiently evoke ferroptotic cell death. The molecular scaffold of ISSM is constructed by conjugating the cyclooxygenase-2 (COX-2) inhibitor indomethacin with an ER-targeting moiety via a disulfide-containing linker. Following cellular internalization and subsequent ER localization, ISSM depletes cellular glutathione (GSH) through the thiol-disulfide exchange reactions, thereby crippling GSH-glutathione peroxidase 4 defense axis. Meanwhile, the released active drug not only elevates the arachidonic acid (AA) levels by inhibiting COX-2, but also induces intense endoplasmic reticulum stress and ROS production. The synergistic effect of these actions drives a robust increase in lipid peroxidation, culminating in potent ferroptotic cell death. This work elucidates an ER-targeting nanotherapeutic strategy that specifically amplifies ferroptosis by concurrently depleting GSH and elevating AA levels, offering a compelling approach for cancer therapy. STATEMENT OF SIGNIFICANCE: Ferroptosis has emerged as a promising strategy for cancer treatment, which damages tumor cells by triggering the lethal accumulation of reactive oxygen species and lipid peroxides. However, the development of efficient ferroptosis-inducing medicines is severely impeded by the unidentified key subcellular sites of lipid peroxidation. In this work, we report an ER-targeting prodrug nanoassembly (ISSM) that synergistically promotes ferroptosis by depleting glutathione and elevating arachidonic acid levels. Here, ISSM simultaneously regulates the defence and execution systems of ferroptosis, leading to robust lipid peroxidation and potent ferroptotic cell death. This work elucidates an ER-targeting nanotherapeutic strategy that specifically amplifies ferroptosis by concurrently depleting glutathione and elevating AA levels, offering a compelling approach for cancer therapy.