Single-Cell Heterogeneity Restorative Chimeric Engineering Nanoparticles for Alleviating Antibody-Mediated Allograft Injury

Abstract

Disturbance of single-cell transcriptional heterogeneity is an inevitable consequence of persistent donor-specific antibody (DSA) production and allosensitization. However, identifying and efficiently clearing allospecific antibody repertoires to restore single-cell transcriptional profiles remain challenging. Here, inspired by the high affinity of natural bacterial proteins for antibodies, a genetic engineered membrane-coated nanoparticle termed as DSA trapper by the engineering chimeric gene of protein A/G with phosphatidylserine ligands for macrophage phagocytosis was reported. It has been shown that DSA trappers adsorbed alloreactive antibodies with high saturation and activated the heterophagic clearance of antibody complexes, alleviating IgG deposition and complement activation. Remarkably, DSA trappers increased the endothelial protective lineages by 8.39-fold, reversed the highly biased cytotoxicity, and promoted the proliferative profiles of Treg cells, directly providing an obligate immune tolerant niche for single-cell heterogeneity restoration. In the mice of allogeneic transplantation, the DSA trapper spared endothelial from inflammatory degenerative rosette, improved the glomerular filtration rate, and prolonged the survival of allogeneic mice from 23.6 to 78.3 days. In general, by identifying the lineage characteristics of rejection-related antibodies, the chimeric engineered DSA trapper realized immunoadsorption and further phagocytosis of alloantibody complexes to restore the single-cell genetic architecture of the allograft, offering a promising prospect for the treatment of alloantibody-mediated immune injury.