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.