Proinflammatory Macrophage-Targeted Nanoparticles Rejuvenate Aged Macrophages and Their Phagocytic Capacity

Aging profoundly compromises immune homeostasis, leaving elderly individuals highly vulnerable to inflammatory diseases. Central to this process is macrophage dysfunction, as macrophages progressively shift toward a pro-inflammatory M1 phenotype with excessive inflammation and impaired phagocytosis. This diminished phagocytic capacity not only weakens host defense but also limits the therapeutic efficacy of nanoparticle (NP)-based antisenescence interventions due to the reduced cellular uptake. Therefore, reversing cellular inflammation and restoring the function of senescent macrophages are crucial in treating inflammatory diseases in the elderly. This article presents an M1-targeted NP to rejuvenate aged macrophages and restore their phagocytosis. Gold nanocages (AuNCs) were camouflaged with <i>E. coli</i>-derived outer membrane vesicles (OMVs) and loaded with dexmedetomidine (dex) to create AuNC-OM-dex. The OMV coating enhanced the uptake of NPs by M1-like aged macrophages through CD64 and CD14-mediated recognition of bacterial membrane components, significantly improving drug delivery efficiency. Once internalized, dex, an anti-inflammatory agent, not only reduced senescence-associated factors but also restored phagocytic function in vitro. Mechanistically, dex rescued phagocytosis in senescent macrophages by suppressing p38-MAPK signaling, a pathway which had not been implicated in age-related phagocytic decline in prior studies. Restoring macrophage phenotype and function enhanced their immunoregulatory capacity, thereby aiding in the control of inflammation in aged inflammatory diseases. Furthermore, AuNC-OM-dex effectively prevented lipopolysaccharide-induced inflammatory bone resorption in an aged mouse model, highlighting its therapeutic potential in vivo. These findings demonstrate a dual-action nanoplatform that both enhances delivery to and rejuvenates aged macrophages, offering a promising therapeutic approach for treating inflammatory diseases associated with aging.