Neuroinflammation and peripheral targeting: formulation-based strategies for modulating the neuroimmune axis in diabetic peripheral neuropathy.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) is a common and disabling complication of diabetes that is largely treated symptomatically. Chronic neuroinflammation in the peripheral nerve, dorsal root ganglion, and blood-nerve barrier (BNB) may contribute to disease progression, making the peripheral neuroimmune interface a potential therapeutic target. AREAS COVERED: A literature search of PubMed/MEDLINE and Google Scholar was conducted for January 2005-July 2026, supplemented by reference-list hand-searching and prioritization of recent studies. This review examines neuroinflammatory mechanisms in DPN, including macrophage activation, Schwann-cell dysfunction, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, and BNB impairment. It also evaluates peripheral-targeted nanomedicine and advanced drug delivery systems, including lipid and polymeric nanoparticles, nanoemulsions, exosomes, hydrogels, and microneedles. EXPERT OPINION: Preclinical evidence suggests that inadequate endoneurial drug exposure is a plausible pharmacokinetic barrier to disease modification in DPN, although its contribution to clinical treatment failure remains unconfirmed. Peripheral-targeted nanomedicine offers a rational strategy to improve drug delivery to regions of neuroinflammation. Standardized preclinical models, sex-specific analyses, biomarker-informed trials, scalable manufacturing, and rigorous clinical validation will be critical for translation.