Spleen‐Targeting Biomimetic Hybrid Nanocarriers for Systemic Immune Reprogramming in Colitis: RBC Membrane Vesicle‐Fused Lipid Nanoparticles

Abstract Current therapeutic strategies for inflammatory bowel disease (IBD) remain limited by broad systemic immunosuppression and insufficient control of immune dysregulation within secondary lymphoid organs, particularly the spleen. To overcome these limitations, a spleen‐targeting immunomodulatory nanoparticle (NP) is developed that delivers rapamycin (RP) loaded red blood cell (RBC) membrane vesicle‐fused lipid nanoparticles (RBC MV ‐LNP‐RP). This NP leverages erythrophagocytosis, the natural clearance mechanism of senescent RBCs, to achieve selective accumulation in the spleen and efficient uptake by splenic macrophages and dendritic cells. This spleen‐targeted delivery of RBC MV ‐LNP‐RP primarily initiates immunomodulation within the spleen, which subsequently leads to systemic immune rebalancing, while minimizing non‐specific immunosuppression and associated adverse effects. In a dextran sulfate sodium (DSS)‐induced murine colitis model, treatment with RBC MV ‐LNP‐RP reprogrammed myeloid cells toward anti‐inflammatory phenotypes, mitigated splenomegaly, and significantly enhanced mucosal regeneration in the colon. These results highlighted the pivotal role of the spleen in IBD pathogenesis and established RBC MV ‐LNP‐RP as a promising candidate for effective immunotherapy. Importantly, this approach offered superior biocompatibility, immune evasion, and organ‐specific immunomodulation, which further supported its potential in IBD treatment. Beyond IBD, this spleen‐targeted immunomodulatory NP may provide a transformative approach for restoring immune homeostasis in chronic inflammatory diseases.