Nanoflower Structured HA-MnO₂-TCPP Nanoplatform for MRI-Guided Synergistic Sonodynamic and Chemodynamic Tumor Therapy

Sonodynamic therapy (SDT) offers a noninvasive strategy for tumor ablation through ultrasound-activated sonosensitizers that generate reactive oxygen species (ROS); however, its therapeutic efficacy is often limited by tumor hypoxia. Herein, we report the rational design of a multifunctional theranostic nanoplatform, HA-MnO₂-TCPP nanoflowers, that integrates active tumor targeting, dual ROS amplification, and magnetic resonance imaging (MRI) guidance for synergistic sonodynamic and chemodynamic therapy. The MnO₂ nanoflowers were loaded with the sonosensitizer 4-carboxyphenyl porphyrin (TCPP) and surface-modified with hyaluronic acid (HA). This design enables CD44 receptor-mediated tumor targeting and tumor microenvironment-responsive degradation. Upon exposure to the mildly acidic and reductive tumor microenvironment, MnO₂ is reduced to Mn²⁺, leading to glutathione depletion, in situ oxygen generation, and alleviation of hypoxia, while the released Mn²⁺ catalyzes Fenton-like reactions to generate highly toxic hydroxyl radicals (^•OH) and simultaneously serves as an efficient T₁-weighted MRI contrast agent. Meanwhile, TCPP enhances singlet oxygen (¹O₂) generation upon ultrasound activation, enabling effective sonodynamic therapy. Through the coordinated activation of SDT and CDT under MRI guidance, HA-MnO₂-TCPP nanoparticles achieve precise and efficient tumor suppression without reliance on photothermal mechanisms. This work provides a robust paradigm for tumor microenvironment-responsive nanotheranostics and highlights the potential of ultrasound-activated strategies for precision cancer therapy.