Intelligent nanoflowers: a full tumor microenvironment-responsive multimodal cancer theranostic nanoplatform.

Although the collaborative therapy of chemotherapy (CT) and photodynamic therapy (PDT) is much more efficient for tumor treatment than monotherapies, premature leakage of drugs from nanocarriers and hypoxia in the tumor microenvironment (TME) result in systemic toxicity and suboptimal therapy efficiency. To overcome these limitations, we developed an intelligent nanoflower composite (termed FHCPC@MnO2) by coating functionalized polyphosphazene on superparamagnetic Fe3O4 nanoclusters and then growing MnO2 nanosheets as an outer shell. The FHCPC@MnO2 nanoflowers with multistage H2O2/pH/GSH-responsive properties could fully exploit TME characteristics, including supernormal glutathione (GSH) levels, low pH and high H2O2, to realize the specific release of drugs in tumors and maximum synergetic therapeutic effects. The MnO2 nanosheets can elevate O2 concentration by catalytic decomposition of H2O2 and can be simultaneously reduced to Mn2+ by overexpressed GSH in the acidic TME. Meanwhile, the inner polyphosphazene containing (bis-(4-hydroxyphenyl)-disulfide) is GSH- and pH-sensitively biodegradable to release the anticancer drug curcumin (CUR) and photosensitizer chlorin e6 (Ce6) in the TME. Therefore, the "triple-responsive" and synergetic strategy simultaneously endows the nanoflowers with specific drug release, relieving hypoxia and the antioxidant capability of the tumor and achieving significant optimization of CT and PDT. In addition, the resulting Mn2+ ions and Fe3O4 core enable in vivo T1/T2 magnetic resonance imaging (MRI), while the released Ce6 can simultaneously provide a fluorescence imaging (FL) function. Unsurprisingly, the intelligent nanoflowers exhibited remarkable multimodal theranostic performance both in vitro and in vivo, suggesting their great potential for precision medicine.