Gold Cube-in-Cube Based Oxygen Nanogenerator: A Theranostic Nanoplatform for Modulating Tumor Microenvironment for Precise Chemo-Phototherapy and Multimodal Imaging

Engineering a versatile oncotherapy nano platform integrating both diagnostic and therapeutic functions has always been an intractable challenge in targeted cancer treatment. Herein, to actualize the theme of precise medicine, a nanoplatform is developed by anchoring Mn-Cdots to doxorubicin (DOX)-loaded mesoporous silica-coated gold cube-in-cubes core/shell nano composites and further conjugating them to a Arg-Gly-Asp (RGD) peptide (denoted as RGD-CCmMC/DOX) to achieve an active-targeting effect. Under 635 nm irradiation, the nanoplatform acts as oxygen nanogenerator that produces 02 in situ and amplifies the content of singlet oxygen (O-1(2)) in the hypoxic tumor microenvironment (TME), which has been demonstrated to attenuate tumor hypoxia and synchronously enhance photodynamic efficacy. Moreover, the gold cube-in-cube core in this work has been proven as a photothermal agent for hyperthermia, which exhibits a favorable photothermal effect with a 65.6% calculated photothermal conversion efficiency under 808 nm irradiation. In addition, the nanoplatform achieves heat- and pH-sensitive drug release with precise control to specific tumor sites, executing combined chemo-phototherapy functions. Besides, it functions as a multimodal bioimaging agent of photothermal, fluorescence, and magnetic resonance imaging for the accurate diagnosis and guidance of therapy. As validated by in vivo and in vitro assays, the TME-responsive nanoplatform is highly biocompatible and effectively obliterates 4T1 tumor xenografts on nude mice after triple-synergetic treatment. This work presents a rational design of versatile nanoplatforms, which modulate the TME to enable high therapeutic performance and multiplexed imaging, which provides an innovative paradigm for targeted tumor therapy.