Engineering a versatile
oncotherapy nanoplatform 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 nanocomposites 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 O2
in situ and amplifies the content of singlet oxygen (1O2) 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.