Multifunctional Mn–Cu Bimetallic <b>DNAsome</b> for Photothermal-Assisted Chemodynamic Cancer Therapy

The efficacy of chemodynamic cancer therapy is drastically reduced due to the sluggish reaction kinetics of Fenton reactions inside the tumor microenvironment (TME). Hence, it is highly desirable to develop strategies that can improve the reaction kinetics of the Fenton reaction at the TME. Herein, a supramolecular approach for the crafting of a DNA-based chemodynamic therapy (CDT) agent containing dual Fenton reaction centers and a photothermal agent (<b>DNA1some/PDMn/DNA2</b>) for the targeted and enhanced chemodynamic cancer therapy is reported. The nanoformulation exhibited targeted cellular internalization via a receptor-mediated endocytosis mechanism and underwent disassembly at the lysosome, leading to the release of individual components of the nanoformulation, which include (i) Cu²⁺, (ii) Mn⁴⁺, and polydopamine. Reduction of Cu²⁺ and Mn⁴⁺ with intracellular GSH yielded two Fenton reaction centers, Cu⁺ and Mn²⁺, respectively, which underwent Fenton reaction with H₂O₂ to produce ^•OH. Further, photoirradiation of the nanoformulation using an 808 nm laser resulted in a photothermal effect due to the presence of polydopamine. This not only facilitates the cellular apoptosis via the photothermal effect but also improves the efficiency of both Cu⁺- and Mn²⁺-based Fenton reactions. The enhanced therapeutic outcome was due to the synergetic combination of PTT and CDT.