MnO2-based nanoparticles remodeling tumor micro-environment to augment sonodynamic immunotherapy against breast cancer†

Abstract

The tumor microenvironment (TME) is characterized by a complex array of factors, including aerobic conditions, high glutathione (GSH) levels, acidic pH, and elevated hydrogen peroxide (H₂O₂) content, all of which promote cancer progression and contribute to poor prognosis. Fortunately, these challenges can be addressed using MnO₂-based nanomaterials. In this study, we have designed and synthesized a Curcumin/MnO₂@PLGA@4T1 cell membrane (CMP@4T1m) system aimed at remodelling the TME and enhancing sonodynamic immunotherapy for breast cancer. Through the homologous targeting ability of 4T1m, CMP@4T1m efficiently accumulates at the tumor site. Upon ultrasound irradiation, curcumin (Cur) acts as a sonosensitizer, generating cytotoxic reactive oxygen species (ROS) that induce immunogenic cell death (ICD), activate T-cell responses, and repolarize protumoral M2-like macrophages to antitumoral M1-like macrophages. In the TME, which is mildly acidic and enriched with GSH and H₂O₂, MnO₂ not only oxidizes GSH to glutathione disulfide (GSSG) but also reacts with H₂O₂ and H⁺ to produce oxygen, alleviating hypoxia and significantly enhancing the sonodynamic immunotherapy effect. Additionally, Mn²⁺ generated during this process converts H₂O₂ into cytotoxic hydroxyl radicals (˙OH). This study thus lays the foundation for advancing cancer nanomedicine, offering a novel approach that integrates TME remodelling with sonodynamic immunotherapy.