Mutually reinforcing nanofactory mimicking controllable “cluster bomb” for synergistic diagnosis and treatment of hypoxic cancer

Multimodal therapy presents one of the most promising strategies for combining multiple therapies to treat the usually complex and insidious tumor tissue. Although multifunctional nanomaterials have been designed for the construction of multimodal therapies, the generally existing inadequate coordination among components might result in low synergistic therapeutic effects and prevent the realization of their full clinical potential. Herein, inspired by the controllable “cluster bomb” model, we designed an intelligent, biocompatible, and multifunctional nanofactory system (PDA@GOx@MnO₂-PEG) that encapsulates a variety of nanoagents to achieve high destruction efficiency against tumor. The stimulus-responsive outer MnO₂ acts as the shell of “bomb” triggering the cascade catalytic reaction and forms a self-sustainable ring catalytic chain with glucose oxidase (GOx). Polydopamine (PDA) as a substrate with excellent protein carrying capacity achieves high GOx loading. Meanwhile, its efficient photothermal conversion efficiency exhibits the potential of low-temperature (∼45°C) to further enhance GOx enzymatic activity. Notably, the internal GOx is like a “sub-bomb” that is released in a controlled manner to increase the accumulation at tumor hypoxic sites, and gives full play to its glucose consumption capacity for starvation therapy under the help of sufficient oxygen and low hyperthermia. In this system, various nanoagents cooperate and advance layer by layer to fully exploit their power, forming a self-sufficient nanofactory model, and achieving excellent low-temperature photothermal-starvation synergistic therapy through a synergistic strategy. Moreover, the nanocomposite exhibits trimodal imaging capability for sensitive diagnosis and real-time monitoring of therapy. This study provides new insights for designing biocompatible and intelligent theranostic nanoplatforms to maximize the multi-modal therapeutic effect in precision medicine. [Figure not available: see fulltext.].