Here, we reveal that age-associated shifts in plasma composition remodel the protein corona of liposomes, leading to divergent biodistribution and immune responses. Using plasma from young (1-month), middle-aged (9-month), and aged (18-month) mice, we demonstrate that liposomes incubated in aged plasma acquire coronas enriched with immunoglobulins, particularly IgG. This age-dependent IgG enrichment enhances macrophage uptake via Fc receptor-mediated endocytosis and amplifies complement activation through the alternative pathway, triggering NF-κB signaling and a pro-inflammatory cascade marked by M1 macrophage polarization.