Prussian Blue-Derived Nanoplatform for In Situ Amplified Photothermal/Chemodynamic/Starvation Therapy

Chemodynamic therapy (CDT) is an emerging tumor treatment; however, it is hindered by insufficient endogenous hydrogen peroxide (H₂O₂) and high glutathione (GSH) concentrations in the tumor microenvironment (TME). Furthermore, CDT has limited therapeutic efficacy as a monotherapy. To overcome these limitations, in this study, a nanoplatform is designed and constructed from Cu-doped mesoporous Prussian blue (CMPB)-encapsulated glucose oxidase (GOx) with a coating of hyaluronic acid (HA) modified with a nitric oxide donor (HN). In the proposed GOx@CMPB-HN nanoparticles, the dopant Cu²⁺ ions are crucial to combining and mutually promoting multiple therapeutic approaches, namely, CDT, photothermal therapy (PTT), and starvation therapy. The dopant Cu²⁺ ions in CMPB protect against reactive oxygen species to deplete the intracellular GSH in the TME. Additionally, the byproduct Cu⁺ ions act as a substrate for a Fenton-like reaction that activates CDT. Moreover, H₂O₂, which is another important substrate, is produced in large quantities through intracellular glucose depletion caused by the nanoparticle-loaded GOx, and the gluconic acid produced in this reaction further enhances the TME acidity and creates a better catalytic environment for CDT. In addition, Cu²⁺ doping greatly improves the mesoporous Prussian blue (MPB) photothermal conversion performance, and the resultant increase in temperature accelerates CDT catalysis. Finally, the HN coating enables the nanoparticles to actively target CD44 receptors in cancer cells and also enhances vascular permeability. Therefore, this coating has multiple effects, such as facilitating enhanced permeability and retention and deep laser penetration. In vitro and in vivo experiments demonstrate that the proposed GOx@CMPB-HN nanoplatform significantly inhibits tumor growth with the help of in situ enhanced synergistic therapies based on the properties of the TME. The developed nanoplatform has the potential to be applied to cancer treatment and introduces new avenues for tumor treatment research.