ABSTRACT Ferroptosis is a promising anticancer strategy, yet its efficacy is limited by insufficient cellular hydrogen peroxide (H 2 O 2 ) 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 Fe 2+ release and amplifies it through the ZnS component. This amplification operates via two mechanisms: hydrogen sulfide (H 2 S)‐mediated catalase (CAT) inhibition elevates H 2 O 2 for the Fenton reaction, while Zn 2+ ‐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.
Yang et al. (Sat,) studied this question.