Supramolecular-orchestrated carrier-free chemodynamic synergists with augmented oxidative damage for potentiated cancer therapy

Abstract

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 supramolecular orchestration of γ-cyclodextrin (γ-CD) with Cu²⁺ and the MTH1 inhibitor TH588, effectively overcoming tumor resistance by greatly amplifying oxidative damage capability. Without additional carriers and mediated by multiple supramolecular 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.