Provoking Potent Cellular Ferroptosis in the Thermo-Sensitive S-Phase via CPT-11 Loaded Janus Nanomedicine for Enhanced Cancer Therapy.

Abstract

Ferroptosis is a promising anticancer strategy, yet its efficacy is limited by insufficient cellular hydrogen peroxide (H₂O₂) levels and intrinsic antioxidant defenses. Meanwhile, mild photothermal therapy (mPTT) enhances ferroptosis by accelerating lipid peroxidation. Herein, we designed a Janus nanoplatform that specifically arrests cells in thermo-vulnerable S-phase to maximize the ferroptosis-sensitizing capacity of mPTT. A Janus architecture with a unique morphology was engineered to incorporate three functional modules: (1) A photothermal half-bowl composed of polydopamine (PDA) that generates localized hyperthermia under near-infrared (NIR) laser irradiation; (2) a drug-loading module utilizing π-π stacking to deliver irinotecan (CPT-11), which arrests the cell cycle at the heat-sensitive S-phase and creates a favorable environment for mPTT; and (3) a ferroptosis-inducing Fe-zinc sulfide (ZnS) core anchored to the other half-bowl, which initiates ferroptosis via Fe²⁺ release and amplifies it through the ZnS component. This amplification operates via two mechanisms: hydrogen sulfide (H₂S)-mediated catalase (CAT) inhibition elevates H₂O₂ for the Fenton reaction, while Zn²⁺-triggered p53 activation suppresses SLC7A11, disrupting the glutathione (GSH)-glutathione peroxidase 4 (GPX4) antioxidant axis. The resulting nanoplatform demonstrated excellent antitumor efficacy, with ferroptosis confirmed as critical to its performance. This Janus nanoplatform presents a novel multi-mechanism cooperative strategy for anticancer therapy centered on ferroptosis.