Rationally designed sonocatalyst-enhanced supramolecular ferroptosis inducers for effective cancer therapy

Ferroptosis is a promising strategy against apoptosis-resistant tumors, yet traditional iron-induced approaches face safety issues and unsatisfied efficacy within complex tumor microenvironments, highlighting the need for biocompatible and highly effective ferroptosis inducers. Herein, we rationally constructed a series of supramolecular ferroptosis inducers (Ru1-Ru3) with sonosensitivity and sonocatalytic properties <i>via</i> molecular engineering, designed for cancer treatment through near-infrared fluorescence-guided sonodynamic therapy. Among them, Ru3 exhibited high ultrasound-triggered ¹O₂ generation efficiency (<i>Φ</i> _Δ = 0.89) owing to its extended π-conjugated system and enhanced intramolecular charge transfer effect. Moreover, Ru3 possesses catalase mimic and peroxidase mimic activities, significantly improving ROS generation and diversifying ROS species. Further studies revealed that Ru3 localized predominantly in lysosomes, where it induced lysosomal membrane permeabilization and activated ferritinophagy under US irradiation, leading to the release of iron ions into the cytosol and triggering a Fenton reaction. Furthermore, Ru3 catalyzed the depletion of GSH and the oxidation of NADPH, disrupting redox homeostasis. These effects collectively suppressed GPX4 activity, promoted lipid LPO accumulation, and ultimately enhanced ferroptosis. <i>In vivo</i> experiments confirmed that US-activated Ru3 effectively inhibited 4T1 tumor growth with favorable biosafety. This work provides a research framework for the design of next generation ferroptosis inducers.