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 (Mn²⁺), which serve as one of the most common transition metal ions, play vital roles in enhancing innate immune responses. However, immune agonists based on Mn²⁺ 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(Mn²⁺) protein nanoparticles (termed as NPs(Mn²⁺)), 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(Mn²⁺) 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 Mn²⁺ and may broaden metal ion clinical use in the field of immunotherapies.