Ultrasound-responsive taurine lipid nanoparticles attenuate oxidative stress and promote macrophage polarization for diabetic wound healing.

Diabetic wound healing presents a significant clinical challenge due to disrupted neuro-immune interactions. This study identifies the α7 nicotinic acetylcholine receptor (α7nAChR) as a key regulator of wound repair by linking cholinergic signaling to macrophage reprogramming. GEO analysis of diabetic foot ulcer (DFU) microenvironments revealed neuronal loss, M1 macrophage dominance, and chronic inflammation, all driven by impaired acetylcholine (ACh) secretion and α7nAChR inactivation. Mechanistically, taurine (TA) restored PC12 cell function under high glucose conditions by activating AMPK, alleviating oxidative and endoplasmic reticulum stress, and promoting ACh production. ACh activated macrophage α7nAChR, modulating M1/M2 polarization through JAK2/STAT3 activation and NF-κB suppression. To enhance TA bioavailability, ultrasound-responsive Ccr2-targeted TA nanoparticles (Ccr2@TA@LNP) were developed for site-specific delivery via Ccl2/Ccr2 chemotaxis. In diabetic neuropathy (DPN) mice, Ccr2@TA@LNP accelerated wound healing by increasing ACh levels, enhancing α7nAChR/CD206 expression, and reducing Ccl2-mediated inflammation. By integrating neuroprotection, macrophage reprogramming, and targeted nanotherapy, this study highlights TA as a multi-target agent that restores neuro-immune balance through the AMPK/α7nAChR/JAK2-STAT3 axis, offering a novel therapeutic strategy for diabetic wound treatment.