Engineered Delivery Systems for Chinese Herbal Medicine in Peripheral Nerve Regeneration: Challenges, Advances, and...

Peripheral neuropathy (PN), characterized by sensory, motor, and autonomic dysfunction, presents a significant therapeutic challenge owing to its diverse etiologies, dynamic spatiotemporal injury microenvironment, and impermeable blood-nerve barrier (BNB). The current treatment is mainly palliative and symptom-focused, and fails to solve the core pathological complexity, including the heterogeneity of nerve injury, the conflicting phases of inflammation, repair, and fibrosis, and the imbalance of the microenvironment in chronic conditions such as diabetes. Chinese herbal medicine (CHM) has multiple benefits including neuroprotective, anti-inflammatory, anti-oxidant, and microenvironmental regulation. However, its clinical translation is hindered by poor bioavailability, non-targeted biodistribution, BNB exclusion, and physicochemical mismatches in multicomponent formulations. Preclinical studies suggest that engineered delivery systems could emerge as a transformative solution to these limitations. Nanocarriers penetrate the BNB via diffusion or ligand-mediated targeting, offering spatiotemporal control through a stimulus-responsive design. Hydrogels align their degradation processes with nerve regeneration and correct the imbalanced microenvironments. Degradable membranes offer localized, sustained release, whereas functionalized nerve conduits address structural defects and improve functional recovery beyond autograft limitations. Despite promising preclinical efficacy, clinical translation faces significant hurdles, including long-term biocompatibility concerns, inconsistent scalability in manufacturing, dosage optimization balancing efficacy and cytotoxicity, dependence on external stimuli, and a lack of standardized regulatory frameworks. Overcoming these challenges requires interdisciplinary collaboration to advance intelligent multifunctional designs, scalable production, and rigorous validations. Based on compelling preclinical data, engineered CHM delivery systems are hypothesized to have enormous potential to transform PN management from palliative care to restorative treatment and establish a new framework in precision neurology.