Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes mellitus, leading to progressive degeneration of peripheral nerves and resulting in chronic pain, sensory loss, and disability. Despite its high prevalence and significant burden, current treatments are largely palliative, as the multifaceted metabolic, inflammatory, and vascular mechanisms that underlie DPN have proven challenging to target with disease-modifying therapies. Extracellular vesicles (EVs, including exosomes) are increasingly recognized for their capacity to mediate intercellular communication and promote tissue repair in various disease contexts. While previous studies have suggested the therapeutic potential of EVs on DPN, the systemic fate of administered EVs and the mechanisms by which they orchestrate repair multiorgan systems remain unclear. Mesenchymal stromal/stem cells (MSCs) are notable for their immunoregulatory properties, making them an attractive and practical source of EVs for translational research. Here, we investigate the action and mechanism of therapeutic EVs derived from MSCs in a mouse model of DPN. Using in vivo imaging, multi-omics analyses, and functional assessments, we define how liver-trophic EVs elicit cross-organ immunomodulation and promote neural repair in diabetic mice.