Tumor microenvironment activated mussel-inspired hollow mesoporous nanotheranostic for enhanced synergistic photodynamic/chemodynamic therapy

Abstract

Anti-tumor therapies reliant on reactive oxygen species (ROS) as primary therapeutic agents face challenges due to a limited oxygen substrate. Photodynamic therapy (PDT) is particularly hindered by inherent hypoxia, while chemodynamic therapy (CDT) encounters obstacles from insufficient endogenous hydrogen peroxide (H₂O₂) levels. In this study, we engineered biodegradable tumor microenvironment (TME)-activated hollow mesoporous MnO₂-based nanotheranostic agents, designated as HAMnO₂A. This construct entails loading artemisinin (ART) into the cavity and surface modification with a mussel-inspired polymer ligand, namely hyaluronic acid-linked poly(ethylene glycol)-diethylenetriamine-conjugated (3,4-dihydroxyphenyl) acetic acid, and the photosensitizer Chlorin e6 (mPEG-HA-Dien-(Dhpa/Ce6)), facilitating dual-modal imaging-guided PDT/CDT synergistic therapy. In vitro experimentation revealed that HAMnO₂A exhibited ideal physiological stability and enhanced cellular uptake capability via CD44-mediated endocytosis. Additionally, it was demonstrated that accelerated endo-lysosomal escape through the pH-dependent protonation of Dien. Within the acidic and highly glutathione (GSH)-rich TME, the active component of HAMnO₂A, MnO₂, underwent decomposition, liberating oxygen and releasing both Mn²⁺ and ART. This process alleviates hypoxia within the tumor region and initiates a Fenton-like reaction through the combination of ART and Mn²⁺, thereby enhancing the effectiveness of PDT and CDT by generating increased singlet oxygen (¹O₂) and hydroxyl radicals (•OH). Moreover, the presence of Mn²⁺ ions enabled the activation of T₁-weighted magnetic resonance imaging. In vivo findings further validated that HAMnO₂A displayed meaningful tumor-targeting capabilities, prolonged circulation time in the bloodstream, and outstanding efficacy in restraining tumor growth while inducing minimal damage to normal tissues. Hence, this nanoplatform serves as an efficient all-in-one solution by facilitating the integration of multiple functions, ultimately enhancing the effectiveness of tumor theranostics.

Keywords: Fluorescence/MR dual imaging; Hollow mesoporous nanosystem; Nanotheranostic; PDT/CDT combination therapy; TME responsive.