A Self-Regenerating Mixed-Valence FeO_x-TiO₂ Nanoplatform for Mitochondrion-Targeted Triple-Modal Cancer Therapy

Reactive oxygen species (ROS) cancer therapy is limited by short ROS lifetime, restricted diffusion, and lack of subcellular targeting. Current approaches physically mix independent components, causing complexity and decoupled actions. To overcome these barriers, we developed a mitochondrion-targeted nanoplatform (FTDT) built on a FeOₓ-TiO₂ composite core with intrinsic mixed-valence Fe²⁺/Fe³⁺ pairs. The FT core acts as photosensitizer, while FeOₓ provides catalase- and peroxidase-like activities, integrating self-oxygenation, antioxidant depletion, self-amplifying redox cycling, photosensitization, photothermal conversion, and organelle anchoring into a single entity.

FTDT was synthesized via a hydrothermal method, PDA coating, and TPP conjugation. Mixed-valence state was confirmed by XPS. Catalase- and peroxidase-like activities were evaluated by O₂ and ∙OH detection. UV-Vis-NIR spectroscopy characterized optical absorption. Photothermal conversion was measured under 808 nm laser. ¹O₂ generation was detected using DPBF. Intracellular hypoxia, ROS, mitochondrial targeting, membrane potential, and lysosomal integrity were assessed by fluorescence microscopy. Cytotoxicity and in vivo efficacy were evaluated in A549 cells and xenograft mice.

FTDT showed a self-amplifying cycle: Fe²⁺ drives ∙OH generation, Fe³⁺ consumes GSH and regenerates Fe²⁺; Fe³⁺ from Fenton reaction replenishes the Fe³⁺ pool. The core converted H₂O₂ to O₂. FT core with PDA-enabled NIR absorption allowed ¹O₂ generation and photothermal conversion. TPP enabled mitochondrial localization, inducing dysfunction, lipid peroxidation, and lysosomal disruption, leading to cell death. In vitro and in vivo studies confirmed antitumor efficacy with good biocompatibility.

By unifying self-oxygenation, antioxidant depletion, self-amplifying redox cycling, photosensitization, photothermal conversion, and organelle anchoring, FTDT offers a clinically translatable strategy to overcome key barriers in ROS-based cancer therapy.