Recent Advances in Metal Complexes and Nanostructured Materials for Enhanced Chemodynamic Therapy

Abstract

Chemodynamic therapy (CDT) is a tumor-specific treatment strategy that employs Fenton or Fenton-like reactions to convert endogenous hydrogen peroxide (H₂O₂) into highly cytotoxic hydroxyl radicals (·OH), thereby amplifying intracellular oxidative stress and inducing tumor cell apoptosis. However, its clinical translation is limited by insufficient endogenous H₂O₂ levels in tumors, suboptimal catalytic efficiency under the mildly acidic tumor microenvironment (TME), and glutathione (GSH)-mediated scavenging of reactive oxygen species (ROS). Addressing these challenges has led to strategic CDT enhancements centered on harnessing endogenous regulators in the TME, like pH, H₂O₂, and GSH. Moreover, CDT has been increasingly integrated with complementary treatment modalities, such as chemotherapy, sonodynamic therapy (SDT), photodynamic therapy (PDT), immunotherapy, and metabolic reprogramming, to achieve synergistic therapeutic outcomes. In this context, the rational design of metal complexes is crucial. Metal ions including Fe²⁺, Cu⁺, and Mn²⁺ play central roles in catalyzing Fenton or Fenton-like reactions. Recent advances in inorganic and coordination chemistry have enabled the design of metal complexes with improved catalytic activity, selectivity, and stability. Furthermore, the development of nanostructured materials, such as metal-organic frameworks (MOFs), porous nanocarriers, and heterojunction nanoparticles, has expanded the possibilities for combining CDT with other therapies. These nanostructures not only serve as efficient carriers for metal complexes but also offer additional functionalities, including targeted drug release, TME modulation, and ROS amplification. This review comprehensively summarizes recent progress in the field, with a focus on mechanistic insights, design principles, and emerging translational opportunities for CDT-based combination therapies.