(Left) Currently available FDA-approved complement therapeutics function via systemic inhibition of complement activation. These include inhibitors of the initiation stage (C1 esterase inhibitors [such as berinert, cinryze, haegarda, or ruconest]) or those targeting C1s (such as sutimlimab), central component C3 (pegceptacoplan), the amplification loop (iptacopan, targeting factor B; danicopan, targeting factor D), or at terminal effector pathways (eculizumab, ravulizumab, or zilucoplan, targeting C5) and C5a signaling (avacopan) (Table 3). (Right) However, given that activation of complement is a local event, there is potential to inhibit complement at the level of the graft to modulate it locally without affecting host systemic complement functions. To date, these approaches have been explored only in experimental transplantation and/or cell culture models. APT070 (mirococept), is a membrane-localizing C3 convertase inhibitor that has been explored in kidney transplantation (120). Due to its unique membrane-interacting synthetic peptide, which mediates binding to phospholipids on the cell surface, it can be perfused into the donor graft to precoat the endothelium prior to transplantation. Recombinant protein (134, 137) and natural antibody single-chain fragment (53) targeting moieties have been used to target complement inhibitors to the graft via binding to complement opsonins or exposure of damage-associated molecular patterns and/or neoantigens that are exposed by ischemia/reperfusion in the graft, respectively. Given the unique structure of the lung, direct targeting of complement can also be achieved by nebulization. Preclinical studies directly nebulizing C3aR antagonist to the donor lung have shown efficacy in reducing IRI and rejection onset (63). While not specifically tested in lung transplantation, epithelial intracellular factor B inhibition (28) and C5aR1 antagonism (33) have shown promise in reducing lung epithelial injury.