Manganese nanodepot augments host immune response against coronavirus

Interferon (IFN) responses are central to host defense against coronavirus and other virus infections. Manganese (Mn) is capable of inducing IFN production, but its applications are limited by nonspecific distributions and neurotoxicity. Here, we exploit chemical engineering strategy to fabricate a nanodepot of manganese (nanoMn) based on Mn(2+). Compared with free Mn(2+), nanoMn enhances cellular uptake and persistent release of Mn(2+) in a pH-sensitive manner, thus strengthening IFN response and eliciting broad-spectrum antiviral effects in vitro and in vivo. Preferentially phagocytosed by macrophages, nanoMn promotes M1 macrophage polarization and recruits monocytes into inflammatory foci, eventually augmenting antiviral immunity and ameliorating coronavirus-induced tissue damage. Besides, nanoMn can also potentiate the development of virus-specific memory T cells and host adaptive immunity through facilitating antigen presentation, suggesting its potential as a vaccine adjuvant. Pharmacokinetic and safety evaluations uncover that nanoMn treatment hardly induces neuroinflammation through limiting neuronal accumulation of manganese. Therefore, nanoMn offers a simple, safe, and robust nanoparticle-based strategy against coronavirus. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (RNA-seq data analysis, IFN and ISGs examination, in vitro viral infection, flow cytometry, ICP-MS, DHE staining, and detection of inflammatory factors) is available in the online version of this article at 10.1007/s12274-020-3243-5.