Modulating Macrophage Polarization for Severe Acute Pancreatitis Therapy via Cisplatin-like Prussian Blue Nanozymes

<b>Rationale:</b> Development of reactive oxygen species (ROS) antioxidants with high biosafety and anti-inflammatory properties for macrophage regulation in severe acute pancreatitis (SAP) therapy remains challenging. Here, we engineered a cisplatin-like calcium hexacyanoferrate Prussian blue nanozyme (Cri-Pt-CaFe_PB) that functioned as a ROS scavenger to modulate macrophage polarization. <b>Methods:</b> The Cri-Pt-CaFe_PB was prepared using a stepwise freeze-thaw method, and its structure and long-term stability were characterized by transmission electron microscope and dynamic light scatting. Subsequently, <i>in vitro</i> experiments were conducted to investigate the cytotoxicity and protective effects of Cri-Pt-CaFe_PB. Fluorescence imaging and ICP-MS were applied to monitor its biodistribution and pharmacokinetics <i>in vivo</i>. Moreover, the biochemical kits, immunofluorescence, hematoxylin-eosin staining, and western blot were utilized to clarify <i>in vivo</i> therapeutic effect of Cri-Pt-CaFe_PB in SAP mice. <b>Results:</b> Pt(VI) precursor was covalently coordinated with ultramicro CaFe_PB nanospheres (~5 nm) and then converted into Pt(II) cisplatin-like nanozyme-based antioxidants, exhibiting exceptional ROS scavenging and anti-inflammatory effects at cellular and molecular levels with no toxicity <i>in vitro</i> or <i>in vivo</i>. Density functional theory simulation reveals the key role of Cri-Pt-CaFe_PB with high peroxidase activity to the anti-inflammation treatment. Remarkably, the Cri-Pt-CaFe_PB can protect the pancreas from oxidative stress damage and induce M1 to M2 macrophages repolarization after intravenous administration by downregulating CD86 protein expression (an M1 marker) and activating Arg-1 protein (an M2 marker), effectively reversing inflammatory damage in SAP and inhibiting the expression of proinflammatory cytokines. <b>Conclusions:</b> This study highlights the feasibility of Cri-Pt-CaFe_PB nanozymes as ROS scavengers to regulate macrophage polarization towards M2 phenotype, which offers a novel effective nanomedicine strategy.