Islet-Targeted ZnT8 Antibodies Protect Pancreatic β-Cells From Inflammatory Stress.

β-Cell maladaptive unfolded protein response is a shared pathogenic feature of type 1 and type 2 diabetes, yet therapeutic strategies that selectively restore β-cell proteostasis remain limited. Zinc transporter 8 (ZnT8) is an islet-restricted endoplasmic reticulum (ER)-resident membrane protein whose folding burden is amplified under inflammatory stress. Here, we show that cell surface-directed ZnT8 antibodies are internalized and act as selective ZnT8 chaperones, preserving β-cell function across multiple diabetes models. ZnT8 chaperoning protected β-cells in prediabetic autoimmune nonobese diabetic (NOD) mice and obesity-associated diabetic mice on an inflammation-prone background, suppressing maladaptive ER stress and MHC class I hyperexpression. In contrast, no protection was observed in inflammation-resistant obesity-associated diabetes or in models of ZnT8-independent proteotoxicity or direct β-cell cytotoxicity, indicating that ZnT8 chaperoning is contingent on ZnT8-associated inflammatory stress. A humanized Fc-silent derivative, Isle43, showed durable pancreatic retention, dose-dependent reversal of new-onset type 1 diabetes in NOD mice, and sustained remission after treatment cessation. In isolated human islets, ZnT8 chaperoning preserved cytokine-induced reductions in ZnT8 and insulin while attenuating HLA class I and binding immunoglobulin protein induction. Notably, programmed death-ligand 1 (PD-L1) was robustly induced independently of cytokine exposure, identifying PD-L1 as a marker of ZnT8 chaperoning. In vivo, Isle43 accumulated in transplanted human islets and preserved graft-dependent glycemic control in diabetic NOD severe combined immunodeficiency recipients. Together, these findings identify ZnT8 folding burden as a key determinant of β-cell proteostasis under inflammatory stress and define islet-targeted ZnT8 chaperoning as a precision strategy for preserving β-cell function in inflammation-dependent diabetes. ARTICLE HIGHLIGHTS: Inflammatory stress increases endoplasmic reticulum protein-folding burden in β-cells and amplifies immunogenicity through HLA-I hyperexpression, yet targeted strategies to restore β-cell proteostasis are lacking. We demonstrate that an islet-specific, cell surface-directed antibody is internalized and functions as a zinc transporter 8-selective chaperone, enhancing endoplasmic reticulum folding capacity, attenuating HLA-I hyperexpression, and robustly inducing programmed death-ligand 1. Identification of programmed death-ligand 1 as a direct pharmacodynamic marker of zinc transporter 8-chaperoning links on-target engagement to reinforcement of local immune checkpoint signaling. Humanized Fc-silent Isle43 shows durable pancreatic retention, dose-dependent reversal of new-onset type 1 diabetes in nonobese diabetic mice, sustained remission after treatment cessation, and protection of human islet graft function in vivo. This islet-targeted strategy preserved β-cell function in inflammatory mouse models and human islet grafts, supporting an islet-targeted therapeutic approach for inflammatory β-cell failure.