Diabetic peripheral neuropathy (DPN) is a major clinical challenge and one of the most common and debilitating complications of diabetes mellitus [1,2]. DPN-associated wounds are characterized by impaired healing, often progressing to chronic ulcers and, in severe cases, leading to limb amputation [3]. The pathophysiology of DPN wounds involves a complex interplay between nerve cells, immune cells, and metabolic disturbances induced by diabetes [4]. Prolonged hyperglycemia disrupts communication between sensory neurons and immune cells, particularly macrophages, impairing both the initiation and resolution of inflammation and tissue regeneration [5,6].

Macrophages play a central role in diabetic wound healing, transitioning between pro-inflammatory M1 and reparative M2 phenotypes [7]. M1 macrophages secrete cytokines like IL-1β and TNF-α, exacerbating tissue damage, while M2 macrophages promote tissue repair and resolve inflammation by secreting anti-inflammatory cytokines such as IL-10, IL-4, and TGF-β1. Under diabetic conditions, the balance between M1 and M2 polarization is disrupted, favoring a pro-inflammatory state that hinders wound healing [8]. Previous studies have demonstrated that activation of the α7 nicotinic acetylcholine receptor (α7nAChR) promotes M2 macrophage polarization and enhances wound healing [9].

Hyperglycemia induces metabolic dysfunction and cellular stress, particularly in neurons, leading to increased oxidative stress and endoplasmic reticulum stress (ERS) [10,11]. ERS, a response to the accumulation of misfolded proteins, contributes to the pathogenesis of diabetes-related complications. In neurons, hyperglycemia-induced ERS disrupts energy metabolism, impairing the synthesis and secretion of neuroprotective factors like acetylcholine (ACh), which is essential for maintaining the neuronal-immune cell axis [12,13]. Reduced ACh levels further hinder M2 macrophage polarization, perpetuating inflammation and delaying wound healing [14].

Taurine (TA), a naturally occurring amino acid, has emerged as a promising therapeutic agent for mitigating ERS and restoring metabolic balance via AMPK activation [15,16]. AMPK activation enhances cellular energy metabolism, promotes cell survival, and modulates inflammation [17]. By alleviating ERS and supporting metabolic function, TA may improve neuronal health and enhance ACh secretion, facilitating M2 macrophage polarization [18,19]. However, the clinical application of TA is limited by its poor bioavailability, due to limited passive diffusion across cell membranes and rapid metabolism. To overcome these limitations, innovative delivery strategies are required.

In this study, we investigated the efficacy of TA in a hyperglycemia-induced stress model using differentiated PC12 cells, focusing on its effects on ERS and metabolic function. Transcriptomic analysis revealed significant upregulation of Ccl2 expression under high-glucose conditions. Ccl2, a chemokine involved in monocyte recruitment, is upregulated in hyperglycemia and plays a key role in mediating inflammation [20,21]. To improve TA bioavailability and enhance localized delivery, we developed Ccl2-chemotactic, Ccr2-targeted, ultrasound-responsive lipid nanoparticles (Ccr2@TA@LNP). This targeted approach modulates stress responses in neuronal cells, promotes ACh secretion, reduces Ccl2 levels, and restores macrophage polarization. Finally, we evaluated the therapeutic potential of Ccr2@TA@LNP in DPN wound models, providing insights into a chemotactic strategy for improving DPN wound healing.