Ferrostatin-1-loaded black phosphorus quantum dots (BPQD@Fer-1) nanodelivery system attenuates T cell-mediated rejection after kidney transplantation.

Abstract

The long-term viability of kidney transplantation is commonly hindered by initial ischemia-reperfusion injury (IRI) and the ensuing T cell-mediated rejection (TCMR). Upon reperfusion, the inevitable IRI provokes an acute surge of reactive oxygen species (ROS), thereby driving profound tubular ferroptosis. Dying cells release damage-associated molecular patterns (DAMPs) that attract alloreactive T cells, intensifying oxidative stress and ferroptosis in a destructive feedback loop. To alleviate the severity of TCMR, we developed ultra-small black phosphorus quantum dots (BPQD) loaded with ferrostatin-1, a ferroptosis inhibitor (BPQD@Fer-1 nanoparticles) delivered directly via ex vivo graft perfusion. Owing to its ultra-small size, BPQD@Fer-1 efficiently accumulates within the renal tubules. This pre-arming strategy enables BPQD@Fer-1 to provide an immediate, synergistic defense: simultaneously quenching the initial ROS storm and blocking downstream lipid peroxidation. In a rat transplant model, preventing early tubular ferroptosis effectively silences DAMP release and cuts off recruitment signals for host T cells. Consequently, BPQD@Fer-1 sharply reduces CD8⁺ T cell infiltration, demonstrating that preemptive ex vivo protection effectively circumvents subsequent immune rejection.