Tumor microenvironment-responsive size-switchable nanoplatforms integrating focused ultrasound achieve highly...

Insufficient intratumoral accumulation and penetration remain major barriers that limit the therapeutic efficacy of nanotechnology-based drug delivery systems (NDDSs). Herein, tumor microenvironment-responsive size-switchable carrier-free nanoplatforms (GMFD NPs) are constructed using glucose oxidase (GOD), Fe³⁺, MnO₂ and doxorubicin (DOX) for focused ultrasound (FUS)-assisted synergistic chemo-starvation therapy. During systemic circulation, GMFD NPs maintain a larger particle size (∼100 nm) to support the enhanced permeability and retention (EPR) effect-mediated tumor accumulation, while FUS increases vascular permeability and provides directional acoustic driving force to further boost their intratumoral accumulation. Subsequently, GMFD NPs gradually disassemble into ultrasmall nanoparticles (20-30 nm) in the acidic tumor microenvironment and realize deep intratumoral penetration. Once internalized by tumor cells, GOD/MnO₂ triggers a cascade-amplifying chain reaction that accelerates glucose depletion, thereby synergizing with DOX to enhance tumor cell killing. Overall, this work provides a promising strategy to overcome the inherent size dilemma between tumor accumulation and deep penetration of NDDSs by integrating FUS with a size-switchable nanoplatform.