DNA Damage and Caspase‑3Apoptosis PathwayDouble-Unlocked Cerium Vanadate Nanorods with Dual-Enzyme Activitiesfor Targeting Mitochondria Therapy

Being able to achieve high Fenton catalytic efficiency at low doses of chemodynamic therapy (CDT) agents is a pressing need in CDT. However, the therapeutic effect of tumors will be severely limited by the inadequate hydrogen peroxide (H₂O₂) generated by aberrant metabolism of tumor cells and lack of mitochondrial targeting of nanoparticles. And only a small amount of nanoparticles can be delivered to the mitochondria. A tailored strategy to specifically increase the Fenton reactivity in tumors is therefore highly desired. Here, cerium vanadate (CeVO₄) nanorods were designed and following amino modification, further altered with 3-hydroxypropyl triphenyl phosphorus bromide (TPP-COOH) and aptamers (Apt) to obtain CeVO₄-TPP nanorods. The TPP group enabled CeVO₄-nanorods to have mitochondrial targeting capability, and Apt promoted the specific entry of CeVO₄-TPP nanorods into MCF-7 cells. The obtained CeVO₄-TPP nanorods demonstrated an enhanced retention at the tumor site for later delivery to the mitochondria. Due to the presence of superoxide dismutase (SOD) activity, CeVO₄-TPP significantly raised the intracellular H₂O₂ level by further converting the superoxide anion radical (O₂^•–) to H₂O₂. Ce⁴⁺ and V⁵⁺ in CeVO₄-TPP nanorods also exhibited good glutathione (GSH) consumption property, and GSH depletion helped tumor cells maintain a comparatively high reactive oxygen species content. Concurrently, Ce⁴⁺ were reduced to Ce³⁺, and V⁵⁺ were reduced to V⁴⁺. The mixed valence states of Ce ions (Ce³⁺ and Ce⁴⁺) and vanadium ion (V⁴⁺) allowed them to function as a Fenton-like catalyst (peroxidase mimetic, POD) that can transform H₂O₂ into harmful hydroxyl radicals (•OH). Through the use of open source and decreased off-target H₂O₂ generation strategies, the increased concentrations of H₂O₂ can undergo the Fenton reaction, resulting in the formation of highly lethal •OH. These potent radicals can trigger extensive apoptosis in cancer cells by causing DNA damage and initiating the caspase-3-mediated apoptosis pathway, ultimately leading to significantly augmented antitumor efficacy. This work presents a typical paradigm to achieve intensive DNA damage and caspase-3 apoptosis pathway double-unlocked efficacy by regulating dual-enzyme activities (SOD-like and POD-like activities) to perturb H₂O₂ homeostasis.