Manganese oxide nanoparticle acts as a promising immune adjuvant via tuning ferroptosis signaling.

While aluminum is one of the most commonly-used adjuvants in vaccine strategies, there are emerging explorations on other metals, which can trigger excellent immunoenhancing effects. Manganese (Mn) as an essential trace metal has been considered to amplify immune responses, however, it is still needed for probing the detailed adjuvant mechanism and functions. This work constructed manganese oxide nanoparticles (Mn NPs) to deliver antigens and revealed that Mn NPs, but not Mn2+ or aluminum, largely promoted antigen uptake, DC maturation, CD4+/CD8+ T cell responses and humoral immune responses, suggesting that nanoparticle form augmented the adjuvanticity of Mn2+. Moreover, these effects were dose-dependent since H-Mn NP with high dosage exerted more remarkable immunoenhancements than L-Mn NP and M-Mn NP. Significantly, it uncovered the adjuvant mechanism involving immune cell death signaling, in which H-Mn NP mitigated the ferroptosis of immune cells to elevate immune responses via crosstalk with STING/NLRP3 signaling. Intriguingly, H-Mn NP triggered adverse effects in ferroptosis, which stimulated ferroptosis in cancer cells to attenuate tumor progression, indicating that the role of Mn NPs in ferroptosis depended on cell types and context. Therefore, it highlighted that manganese oxide nanoparticles possessed extraordinary adjuvant capacity for vaccine efficacy and anti-tumor immunotherapy mainly through ferroptosis signaling.