TH 588

Metal ions trigger Fenton/Fenton-like reactions, generating highly toxic hydroxyl radicals (.OH) for chemodynamic therapy (CDT), which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis.However, tumor cells can counteract this damage through repair pathways, particularly MutT homolog 1 (MTH1) protein attenuation of oxidative DNA damage.Suppression of MTH1 can enhance CDT efficacy, therefore, orderly integrating Fenton/Fenton-like agents with an MTH1 inhibitor is expected to significantly augment CDT effectiveness.Carrier-free CuTH@CD, self-assembled through the supramol. orchestration of γ-cyclodextrin (γ-CD) with Cu2+ and the MTH1 inhibitor TH588, effectively overcoming tumor resistance by greatly amplifying oxidative damage capability.Without addnl. carriers and mediated by multiple supramol. regulatory effects, CuTH@CD enables high drug loading content, stability, and uniform size distribution.Upon internalization by tumor cells, CuTH@CD invalidates repair pathways through Cu2+-mediated glutathione (GSH) depletion and TH588-mediated MTH1 inhibition.Meanwhile, both generated Cu+ ions and existing ones within the nanoassembly initiate a Fenton-like reaction, leading to the accumulation of .OH.This strategy enhances CDT efficiency with minimal side effects, improving oxidative damage potency and advancing self-delivery nanoplatforms for developing effective chemodynamic tumor therapies.

Chemo-dynamic therapy (CDT) has a great potential in tumor extirpation. It entails producing hypertoxic reactive oxygen species (ROS) that damage the DNA of tumor cells and other biomacromolecules. However, the efficiency of CDT is severely hampered by the massive presence of glutathione (GSH) in tumor cells and the interference of ROS defense systems, such as Mutt homolog 1 (MTH1) protein sanitizes ROS-oxidized nucleotide pools. In this research, DNA-mediated self-assembly nanoparticles (HTCG@TA NPs) were engineered with high-performance amplified oxidative damage and gene therapy effect for synergistic anti-tumor treatment. Cu²⁺ was converted into Cu ⁺ by redox reactions to deplete GSH while H₂O₂ was catalyzed to generate hydroxyl radicals (·OH). As a result, the ROS level was evidently improved. Moreover, controllable-released TH588 prevented MTH1-mediated DNA repairing, thus aggravated oxidative damage to tumor cells. Meanwhile, the released functional nucleic acid G3139 downregulated the expression of Bcl-2, and accelerated the apoptosis of tumor cells. In conclusion, the HTCG@TA demonstrated significant effect in oxidative damage amplification and tumor inhibition both in vitro and in vivo, which has provided a new outlook for the clinical application of chemo-dynamic tumor treatment and synergistic gene therapy with self-delivery nanoplatforms.