A Novel Manganese Ion Delivery Carrier Promotes Immune Cell Proliferation and Enhances Innate Immune Responses.

Manganese is a transition metal that is an essential trace element for human health. Manganese ions (Mn), which serve as one of the most common transition metal ions, play vital roles in enhancing innate immune responses. However, immune agonists based on Mn are poorly utilized in clinical trials due to poor chemodynamics and adverse events. In this work, we designed a novel delivery carrier for loading manganese ions by constructing hFn-MT3(Mn) protein nanoparticles (termed as NPs(Mn)), which contained human ferritin heavy chain (hFn) and metallothionein-3 (MT3), induced by isopropyl β-d-thiogalactoside (IPTG) and manganese ions in the prokaryotic expression system. The NPs(Mn) protein nanoparticles could not only stimulate immune cell proliferation but also activate innate immune responses via the cGAS-STING-IRF3 signaling pathway. Collectively, our results unveil a candidate strategy for delivering metal ions beyond Mn and may broaden metal ion clinical use in the field of immunotherapies.