Tumor Microenvironment Stimuli-Responsive Polypeptide Manganese–Calcium Nanomodulator Orchestrating Chemodynamic Therapy and Alleviating Hypoxia in Tumors

It is challenging to develop multiresponsive polypeptide theranostics that can respond to the tumor microenvironment (TME) for highly efficient chemodynamic therapy (CDT) while simultaneously alleviating tumor hypoxia. Inspired by protein biomineralization and utilizing zwitterionic phosphorylcholine-bearing polycysteine as a multivalent template, herein, a kind of MnO x /CaCO 3 -embedded polypeptide nanomodulator (PCMC) was easily constructed by a one-pot method. Upon the redox reaction of MnO x with intracellular glutathione (GSH), released Mn 2+ mediated a Fenton-like reaction to transform endogenous H 2 O 2 into cytotoxic ·OH, enabling GSH depletion-enhanced CDT, while MnO x also consumed H 2 O 2 into O 2 to relieve hypoxia. Meanwhile, the Ca 2+ release from CaCO 3 in the PCMC induced calcium overload to generate reactive oxygen species (ROS), synergizing with MnO x to boost CDT for killing 4T1 cells. The hypoxia staining assay and intracellular GSH and Ca 2+ measurements corroborated that the PCMC effectively alleviated hypoxia and depleted intracellular GSH while inducing calcium overload in 4T1 cells. Remarkably, PCMC could accumulate in tumors, implement a T 1 -weighted magnetic resonance imaging (MRI) in 4T1 tumor-bearing mice, and achieve a synergistic CDT antitumor efficacy while heavily alleviating tumor hypoxia, as evidenced by means of H&E, TUNEL, ROS, and HIF-1α assays. Importantly, this work offers a versatile strategy for designing the TME-responsive polypeptide/metal ion hybrid nanoparticles to amplify CDT and alleviate hypoxia in tumors, opening an avenue for the MRI-guided drug/dye-free cancer theranostics.