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.
- 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.
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