Developing new strategies to overcome biological barriers and achieve efficient delivery of therapeutic nanoparticles (NPs) is the key to achieve positive therapeutic outcomes in nanomedicine. Herein, a multistage-responsive clustered nanosystem is designed to systematically resolve the multiple tumor biological barriers conflict between the enhanced permeability retention (EPR) effect and spatially uniform penetration of the nanoparticles. The nanosystem with desirable diameter (initial size of ~50 nm), which is favorable for long blood circulation and high propensity of extravasation through tumor vascular interstices, can accumulate effectively around the tumor tissue through the EPR effect. Then, these pH-responsive nanoparticles are conglomerated to form large-sized aggregates (~1000 nm) in the tumor under the acidic microenvironment, and demonstrated great tumor retention. Subsequently, the photothermal treatment disperses the aggregates to be ultrasmall gold nanoclusters (~5 nm), thereby improving their tumor penetration ability, and enhancing the radiotherapeutic effect by radiosensitizer. In 4T1 tumor model, this nanosystem shows great tumor accumulation and penetration, and the tumor growth and the lung/liver metastasis in particle/PTT/RT treated mice is significantly inhibited. As a photoacoustic/fluorescence imaging agent and PT/RT synergistic agent, this pH-/laser-triggered size multistage-responsive nanosystem displayes both great tumor accumulation and penetration abilities, and shows excellent potential in tumor therapy.

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