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It is a long-pursued goal to construct various smart theranostics nanoplatforms by facile and repeatable method for personalized tumor treatment. Herein, we employed novel alkyne-phenol and alkyne-amine click-reaction to fabricate responsively biodegradable and multimodal polymeric nanoplatforms for magnetic resonance imaging (MRI) guided effective chemotherapy. The antitumor drug doxorubicin (DOX) and some essential amino acid such as lysine could react with trimethylolpropane tripropiolate (TMP) in a quite mild conditions (room temperature and weak alkaline) by facile click-reactions to give polyprodrugs, the carboxyl and excess amino groups on LTD tended to further coordinate with Mn2+ to afforded metal-coordinated-polyprodrugs (termed as LTD@Mn2+). The resulting LTD@Mn2+ nanoparticles have high covalently drug loading ratio (up to 35%), and could effectively and responsively release DOX and Mn2+ in the acidic environment of tumor cells (extracellular pH ~6.8, endosomes and lysosomes pH ~5.0), because the resulting vinyl-ether and vinyl-amino bonds in LTD@Mn2+ are stable in neutral physiological environment but tend to be broken in acidic conditions. The smart LTD@Mn2+ nanoplatforms not only showed significant tumor inhibit efficiency and negligible damage to normal tissues both in vitro and in vivo due to the high drug loading ratio and controlled release properties, but also provided satisfied MRI quality for assessment the treatment effect because of the magnetic nature of Mn2+. Thus, the metal-ligated polyprodrug suggests a new strategy for the simple and repeatable preparation of polyprodrugs for precise and personalized treatment of tumors.

It is of great importance to develop tumor microenvironment (TME) responsive and adjustable theranostic nano-systems for specific and efficient cancer treatment. However, carrier-based nanomedicines are often inefficacious in vivo due to low drug-loading efficiency, lack of synergistic effects, poor targeting specificity and limited drug accumulation in tumor tissues. Herein, we report a new multimodal theranostic nanoplatform which is assembled from Fe3O4 nanoclusters, MnO2 nanosheets with multifunctional and cross-linked polyphosphazene. This peanut-like nanoplatform exhibited enhanced chemo/photodynamic therapy (CT/PDT) effect as well as significant tumor-targeting capacity. In addition, Fe3O4 cores and MnO2 nanoshells enables T1/T2 magnetic resonance imaging (MRI) of tumor tissues, while photosensitizer methylene blue (MB) allows for fluorescence imaging and PDT simultaneously. Importantly, nanopeanut agents could dual-regulate intracellular oxygen and glutathione (GSH) levels in TME by MnO2 shells, to relieve hypoxic condition and produce enough ROS to induce cell apoptosis. Our research demonstrated that the multistage TME-responsive nanoplatform is ideally suitable for tumor specific drug delivery and real-time disease tracking with enhanced theranostic properties.