Engineered Nanosponge Platform Corrects TLR7‐Related Efferocytosis and Platelet‐Activation for Treatment of Different Systemic Lupus Erythematosus Stages

Abstract Driven by abnormal activation of Toll‐like receptor 7 (TLR7), systemic lupus erythematosus (SLE) exhibits severe efferocytosis impairment of macrophages, leading to the accumulation of antigenic substances and an imbalance of cellular homeostasis in other immune cells, with the most pronounced effect on platelets. While the macrophage‐platelet feedback loop exists, solely restoring impaired efferocytosis of macrophages is insufficient to fully recover platelet levels in SLE. To rescue the disrupted immunity, two cell membrane‐biomimetic nano‐systems are designed: i) an engineered macrophage membrane‐coated nanosponge carrying TLR7 inhibitors that specifically target inflammatory sites; ii) a resting platelet membrane‐coated biomimetic nano‐platform loaded with platelet activation inhibitors. The drug‐loading nanosponge selectively adsorbs pro‐inflammatory cytokines while targeting and repairing impaired efferocytosis. In parallel, the platelet membrane‐coated nano‐platform precisely targets activated platelets, effectively inhibiting their activation. The combined engineered nanosponge platform application mitigates inflammatory cell infiltration, upregulates Treg cells levels, which inhibits immune system hyperactivation, and restores key SLE‐related indicators, alleviating SLE complications such as lupus nephritis and thrombocytopenia in different disease courses of SLE. Overall, the study not only discloses the association between TLR7 and efferocytosis, but also pioneers the treatment of SLE via inhibiting macrophage TLR7 and platelet‐activating, offering novel therapeutic insights for SLE management.