A Multifunctional Nanozyme-Based mRNA Delivery Platform Restores Neurovascular and Sudomotor Function in Diabetic Neuropathy.

Diabetic sudomotor dysfunction, one of the most prevalent complications of diabetic neuropathy (DN), is characterized by impaired sweating due to degenerative changes in sweat glands (SGs) and associated neurovascular networks. Despite its clinical significance, effective treatments remain elusive. Here, we present a multifunctional nanozyme-based platform, Au@Pt coated with ethanolamine-functionalized poly(glycidyl methacrylate) (PGEA), yielding Au@Pt-PGEA (APP), for the efficient delivery of therapeutic nerve growth factor (NGF)-encoding mRNA to modulate the pathological microenvironment and restore SG function. APP exhibits glucose oxidase-like catalytic activity, reactive oxygen species scavenging, oxygen generation, and electroactive properties, collectively reducing oxidative stress and improving the biochemical conditions that constrain tissue repair. When complexed with Ngf mRNA, the resulting APP/Ngf mRNA complex (APPN) promotes endothelial angiogenic responses, induces repair-associated activation of Schwann cells, and enhances neurite outgrowth in vitro. In a late-stage DN murine model, APPN treatment significantly increases perfusion and sweat output, enhances neurovascular reconstruction, and restores SG structural and functional markers. Transcriptomic profiling further reveals APPN-mediated shifts toward reduced inflammatory programs and enhanced pathways linked to oxidative metabolism, tissue regeneration, and peripheral nervous system development. This work establishes a combined strategy for diabetic sudomotor dysfunction through multifunctional nanozyme-mediated gene therapy, underscoring its clinical potential in regenerative medicine.