ARA290 microneedle patch modulate microglia polarization and mitigate diabetic peripheral neuropathy

• The microneedle patch consist of ARA290-loaded hydrogel-forming tips and a soluble backing. • The microneedle patch exhibits high biocompatibility, and minimal skin irritation. • Sustained ARA290 release via microneedles promotes M2 microglia polarization and reduces neuroinflammation. • The microneedle patch effectively alleviates allodynia and improves nerve morphology in a diabetic neuropathy rat model. Diabetic peripheral neuropathy (DPN) causes persistent pain and sensory dysfunction due to neuroinflammation, where pro-inflammatory microglial polarization is a key therapeutic target. ARA290, a peptide derived from erythropoietin with non-hematopoietic activity, offers neuroprotection and pain relief. However, its clinical utility has been constrained by intrinsic peptide limitations in administration and pharmacokinetics. To overcome this, we developed a biocompatible polymeric microneedle (MN) patch. This patch features hydrogel-forming tips loaded with ARA290 and a soluble backing, enabling sustained drug release upon dermal insertion with minimal irritation. In DPN model rats, the MN patches induced significantly early reductions in allodynia and hyperalgesia. Electrophysiological and histological assessments showed improved nerve conduction velocity and intraepidermal nerve density, respectively. Notably, sustained release promoted anti-inflammatory (M2) microglial polarization, reducing central neuroinflammation. Collectively, this MN patch-based strategy effectively alleviates peripheral neuropathy and inhibits central sensitization, offering a promising approach for advanced DPN treatment.