Acid-Responsive Zeolitic Imidazolate Framework-8 Core-Shell Nanovesicles Loaded with Interleukin-2 Nanoplatforms Selectively Expand Regulatory T Cells to Reconstruct Immunometabolic Homeostasis in Diabetic Neuropathy.

This study presents a nanotherapeutic strategy for diabetic peripheral neuropathy (DPN) by developing polyimide-coated zeolitic imidazolate framework-8 core-shell nanovesicles loaded with interleukin-2 (MOF@PI-IL2) for inflammation-microenvironment-responsive delivery of IL-2 and relatively preferential activation of regulatory T cells (Treg cells). Given that DPN is characterized by chronic neuroinflammation and immune dysregulation with impaired Treg cell numbers and activity, the engineered nanoparticles promote Treg cell expansion and immunometabolic reprogramming while suppressing CD8+ T cell cytotoxicity. Through comprehensive evaluation using multiomics integration, biomineralization synthesis, inflammatory models, and DPN mouse experiments, the system demonstrated favorable physicochemical properties and biodistribution. Treatment with MOF@PI-IL2 significantly improved both electrophysiological parameters and structural nerve function. Forkhead box P3 knockdown experiments confirmed that the therapeutic effects were Treg cell dependent. Multiomics analysis further suggested that the treatment partly corrected short-chain fatty acid and tryptophan metabolic dysregulation and was associated with reconstruction of correlations within a "metabolism-IL-2 response-Treg cell module". This work provides an inflammation-microenvironment-responsive and translatable Treg-cell-targeted nanoimmunotherapeutic strategy for DPN while broadening the conceptual framework for treating chronic inflammatory diseases through immunometabolic modulation.