Liver fibrosis (LF) afflicts millions of patients worldwide, yet a universally accepted standard therapy remains elusive. Notably, an elevation of profibrotic monocytes is observed in peripheral blood of LF patients. Inspired by the spleen's reported "accomplice" role in LF development and its monocyte reservoir function, the mechanism of spleen-liver co-morbidity is further explored, unveiling an innovative therapy strategy for LF. In detail, exosomes are prepared from macrophages with low expression of lymphocyte antigen 6 complex locus C (ly6clowExo), low Exo), showcasing a distinctive ability to accumulate simultaneously in both spleen and liver. The ly6clowExo low Exo treatment reduces profibrotic monocyte proportion in spleen, decreases the circulating profibrotic monocytes, and reshapes hepatic immune microenvironment including macrophages, T cells, and natural killer cells. Such synergistic modulation culminates in the reduction of extracellular matrix, achieving satisfying therapeutic outcomes in LF model. Furthermore, the exosome therapeutic is iterated via loading pirfenidone into ly6clowExo. low Exo. A cooperation of two distinct mechanisms is thus achieved by combining the ly6clowExo low Exo immunoregulation with pirfenidone-mediated transforming growth factor-beta pathway inhibition, resulting in an enhanced antifibrotic effect in severe LF model. The ly6clowExo low Exo platform described, with its remarkable capacity for dual- accumulation, multifunctional immunoregulatory capabilities, and drug-loading property, presents extensive clinical application prospects for LF treatment.