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

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.