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

Abstract

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. 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. 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. Diabetic peripheral neuropathy (DPN) is a nerve injury that occurs in the peripheral nerves due to high blood sugar from diabetes. DPN may cause pain, numbness, tingling and loss of sensation in the feet and legs. Most of the current medications only treat the pain, but not the nerve damage. A possible explanation is that drugs delivered via the intravenous route don’t reach damaged nerves in sufficient quantities. This review will look at the possibility of damage caused to nerves that can result from the inflammation surrounding them, changes to the protective blood vessels that supply them, and the interactions between the nerve cells, the supporting cells, and immune cells. It also considers the use of small drug carriers and other local delivery systems to deliver medicines to closer to nerves or cells affected. Initial research indicates that these methods could enhance exposure to the drug and decrease inflammation, although the majority of evidence so far comes from laboratory and animal research. These methods need to be improved to be effective treatments for people who suffer from diabetic nerve damage, and they must be carefully tested for safety, manufactured consistently, and thoroughly tested in clinical trials.