Ultrasound‐Activatable g‐C3N4‐Anchored Titania Heterojunction as an Intracellular Redox Homeostasis Perturbator for Augmented Oncotherapy

Abstract Energy band structure of inorganic nano‐sonosensitizers is usually optimized by surface decoration with noble metals or metal oxide semiconductors, aiming to enhance interfacial charge transfer, augment spin‐flip and promote radical generation. To avoid potential biohazards of metallic elements, herein, metal‐free graphitic carbon nitride quantum dots (g‐C 3 N 4 QDs) are anchored onto hollow mesoporous TiO 2 nanostructure to formulate TiO 2 @g‐C 3 N 4 heterojunction. The direct Z‐scheme charge transfer significantly improves the separation/recombination dynamics of electron/hole (e − /h + ) pairs upon ultrasound (US) stimulation, which promotes the yield of singlet oxygen ( 1 O 2 ) and hydroxyl radicals (·OH). The conjugated g‐C 3 N 4 QDs with peroxidase‐mimic activity further react with the elevated endogenous H 2 O 2 and aggravate oxidative stress. After loading prodrug romidepsin (RMD) in TiO 2 @g‐C 3 N 4 , stimulus‐responsive drug delivery can be realized by US irradiation. The disulfide bridge of the released RMD tends to be reduced by glutathione (GSH) into a monocyclic dithiol, which arrests cell cycle in G2/M phase and evokes apoptosis through enhanced histone acetylation. Importantly, reactive oxygen species accumulation accompanied by GSH depletion is devoted to deleterious redox dyshomeostasis, leading to augmented systemic oncotherapy by eliciting antitumor immunity. Collectively, this paradigm provides useful insights in optimizing the performance of TiO 2 ‐based nano‐sonosensitizers for tackling critical diseases.