Harnessing spatiotemporal melatonin delivery from engineered platforms for targeted microenvironment remodeling in peripheral neuropathy

Peripheral neuropathy, a leading contributor to global disability, arises from persistent neuroinflammation and oxidative stress that progressively dismantle neural support structures. Notably, its pathophysiology is intricately modulated by circadian rhythms. In this context, the endogenous hormone melatonin offers a compelling therapeutic opportunity, given its capacity to orchestrate protective responses across diverse neural cell types. Despite this potential, clinical translation is severely constrained by its suboptimal pharmacokinetic profile. This limitation creates an imperative for innovative biomaterial-based interventions. This review bridges mechanistic insight with engineering design by detailing strategies to achieve spatiotemporally controlled melatonin release through tailored material composition, structural design, and degradation behavior. For traumatic nerve injuries requiring guided regeneration, we examine the utility of implantable conduits. In addressing diffuse neuropathies, we further propose translating these core design principles toward minimally invasive platforms, including injectable hydrogels, microneedles, nanocarriers, and localized depots. The review culminates in a translational roadmap that outlines critical phases for clinical adoption. These phases encompass platform optimization, formulation standardization, rigorous validation of release kinetics, navigation of regulatory pathways for combination products, and the ultimate demonstration of clinical relevance.