Manganese@Albumin Nanocomplex and Its Assembled Nanowire Activate TLR4‐Dependent Signaling Cascades of Macrophages

Abstract The immunomodulatory effect of divalent manganese cations (Mn2+), such as activation of the cGAS−STING pathway or NLRP3 inflammasomes, positions them as adjuvants for cancer immunotherapy. In this study, it is found that trace Mn2+ ions, bound to bovine serum albumin (BSA) to form Mn@BSA nanocomplexes, stimulate pro‐inflammatory responses in human‐ or murine‐derived macrophages through TLR4‐mediated signaling cascades. Building on this, the assembly of Mn@BSA nanocomplexes to obtain nanowire structures enables stronger and longer‐lasting immunostimulation of macrophages by regulating phagocytosis. Furthermore, Mn@BSA nanocomplexes and their nanowires efficiently activate peritoneal macrophages, reprogramme tumor‐associated macrophages, and inhibit the growth of melanoma tumors in vivo. They also show better biosafety for potential clinical applications compared to typical TLR4 agonists such as lipopolysaccharides. Accordingly, the findings provide insights into the mechanism of metalloalbumin complexes as potential TLR agonists that activate macrophage polarization and highlight the importance of their nanostructures in regulating macrophage‐mediated innate immunity.