Aptamer-Driven Immunomodulation of Human Islets: Combating IBMIR for Clinical Translation

Introduction and Objective: Instant blood-mediated inflammatory reaction (IBMIR) causes rapid loss of up to 50% of transplanted islet mass, primarily through inflammatory and coagulation pathways. Blocking these mediators is critical for improving graft survival. We hypothesized that aptamers targeting interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNFα), and factor VIIa (FVIIa) could attenuate IBMIR and improve islet engraftment. Methods: Aptamers were characterized for binding affinity using single-molecule FRET and NMR. Human islets were surface-functionalized with aptamers via Bissulfosuccinimidyl Suberate (BS3) crosslinking without compromising viability or insulin secretion. In vitro assays assessed cytokine-induced injury and gene expression of inflammatory and apoptotic markers by qPCR. Anticoagulant activity of FVIIa aptamer was evaluated through thrombin-antithrombin complex formation and prothrombin time. In vivo efficacy was tested following intraportal transplantation of aptamer-coated islets into nude mice. Results: All aptamers exhibited strong target binding (low micromolar Kd). Immobilization preserved aptamer activity and islet viability. IL-1β and TNFα aptamers significantly suppressed cytokine-driven inflammatory and apoptotic gene expression, while FVIIa aptamer prolonged prothrombin time in a dose-dependent manner. In vivo, aptamer-coated islets demonstrated reduced IBMIR and improved engraftment compared to controls. Conclusion: Surface immobilization of anti-inflammatory and anticoagulant aptamers offers a rapid, clinically translatable strategy to minimize IBMIR and improve early graft survival. This approach integrates seamlessly into current workflows and warrants further evaluation in allogeneic transplantation settings. Disclosure: J. Kalivarathan: None. M. Kanak: None. R. Rabara: None. Funding: U.S. Department of Defense (W81XWH2210102)