SUMMARY Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short- term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T cell (Treg) expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6 specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimunnotherapy resulted in indefinite allograft survival. Together, we show that HDL- based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.

Highlights d We have developed a trained immunity-inducing nanobiologic therapeutic named MTP-HDL d MTP-HDL favorably accumulates in hematopoietic organs of mice and non-human primates d MTP-HDL nanotherapy induces trained immunity through bone marrow progenitors in vivo d MTP-HDL nanotherapy inhibits tumor growth and potentiates immune checkpoint inhibition