Manganese-Based Nanoplatform As Metal Ion-Enhanced ROS Generator for Combined Chemodynamic/Photodynamic Therapy

Reactive oxygen species (ROS) with strong oxidizing and high activity have been regarded as an effective "weapon" for antitumor therapy, since it can induce organelle injury, oxidative damage, and cell death. Herein, hollow structured manganese carbonate (MnCO₃) nanocubes are fabricated and loaded with photosensitizer (chlorin e6, Ce6), obtaining a responsive nanoplatform H-MnCO₃/Ce6-PEG (HMCP NCs). Two different approaches to upregulate intracellular ROS level were realized by HMCP NCs. On one hand, with irradiation of external laser, Ce6 could generate singlet oxygen (¹O₂) through a multistep photochemical process applied in photodynamic therapy (PDT). On the other hand, MnCO₃ could be specifically degraded into Mn²⁺ in an acidic tumor microenvironment (TME), triggering Mn²⁺-activated Fenton-like reaction to convert endogenous H₂O₂ into hydroxyl radical (•OH). In vitro combined chemodynamic therapy (CDT) and PDT showed that the metal ion-enhanced ROS production could break the intracellular redox equilibrium, thus leading to cell death. In vivo combined CDT/PDT with HMCP NCs exhibited remarkably enhanced therapeutic efficacy in inhibiting tumor growth, without resulting in noticeable damage to normal tissues. This work presents a unique type of manganese-based nanoplatform for efficiently generating ROS in solid tumors, favorable for ROS-involved therapeutic strategies.