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 MnOx/CaCO₃-embedded polypeptide nanomodulator (PCMC) was easily constructed by a one-pot method. Upon the redox reaction of MnOx with intracellular glutathione (GSH), released Mn²⁺ mediated a Fenton-like reaction to transform endogenous H₂O₂ into cytotoxic ·OH, enabling GSH depletion-enhanced CDT, while MnOx also consumed H₂O₂ into O₂ to relieve hypoxia. Meanwhile, the Ca²⁺ release from CaCO₃ in the PCMC induced calcium overload to generate reactive oxygen species (ROS), synergizing with MnOx to boost CDT for killing 4T1 cells. The hypoxia staining assay and intracellular GSH and Ca²⁺ 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 T₁-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.