Intraorgan and targeted nanodelivery in organ transplantation of nonhuman primates

Although systemic immunosuppression is standard in transplantation, it carries substantial toxicity and does not achieve adequate drug delivery to key immunologic sites. Nanoparticles (NPs) can enable targeted local immunomodulation with reduced systemic exposure. We evaluated the feasibility of NP delivery to the 2 principal sites of alloimmunity: the donor organ and the recipient lymph nodes (LNs). For intraorgan delivery, we have synthesized and characterized a poly(d,l-lactic-co-glycolic) acid-based NP platform to encapsulate tocilizumab (TCZ). NP-TCZ shows a uniform diameter of ∼100 nm and releases TCZ at a controlled rate with a half-life of 3.4 days. NP-TCZ showed stronger inhibition of lipopolysaccharide-induced interleukin 8, interleukin 1β, and tumor necrosis factor α production from human macrophages compared with free TCZ. In a nonhuman primate (NHP) ex vivo lung perfusion model, fluorescent-labeled NPs were observed to enter human leukocyte antigen-DR isotype⁺, CD11b⁺, and CD20⁺ immune cells of the lung parenchyma and graft-associated LNs. To test delivery to recipient LNs after transplantation, we synthesized large-scale NPs conjugated with MECA79 to target high endothelial venules in draining LNs. MECA79-NPs administered systemically in NHP skin allograft models accumulated in draining LNs at levels 17-fold higher than in nondraining nodes and localized to macrophages adjacent to high endothelial venules. These findings demonstrated the feasibility of nanotherapeutics in NHP transplantation.