Dual-enhanced transdermal delivery: Magnolol-borneol nanoparticle hydrogel for topical treatment of diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) remains a prevalent and challenging complication of diabetes with limited therapeutic options. Magnolol (Mag), a natural multi-target agent, demonstrates significant potential in managing DPN through synergistic anti-inflammatory, antioxidant, and neurorestorative properties. However, its poor oral bioavailability and limited skin penetration hinder clinical application. To address these challenges, we developed a novel topical nanogel system for enhanced transdermal delivery of Mag. Borneol (Bor), a potent penetration enhancer, was co-assembled with Mag via antisolvent precipitation to form self-assembled nanoparticles (Mag-Bor NPs), which were further encapsulated into a carbomer hydrogel matrix to construct the Mag-Bor nanogel (Mag-Bor NPs Gel). The resulting formulation exhibited markedly improved skin permeability and sustained drug retention. Upon topical administration, Mag-Bor NPs Gel effectively alleviated neuropathic impairments in DPN rats through a “transdermal enhancement – anti-inflammatory – nerve repair” mechanism. This therapeutic strategy comprehensively improved key pathological indicators, including plantar thermal, mechanical pain sensitivity, motor nerve conduction velocity (MNCV), intraepidermal nerve fiber density (IENFD), sciatic nerve myelin structure, and inflammation levels in dorsal root ganglia (DRG). This study is the first to report a nanogel system combining efficient transdermal delivery and neurorestorative functions, offering a novel and promising strategy for topical DPN treatment.