Cell-derived exosome therapy for diabetic peripheral neuropathy: a preclinical animal studies systematic review and meta-analysis.

Backgrounds: Exosomes is a promising cell-free therapy for Diabetic peripheral neuropathy (DPN) that imposes long-term negative effects on patients' finances, mental health, and quality of life. We conducted a meta-analysis to assess the therapeutic effects of exosomes (such as SCs-derived, FCs-derived, BMSCs-derived, MSCs-derived, and Plasma-derived) on DPN.

Methods: We searched nine databases from inception to February 2025, then two researchers independently screened studies, extracted data, and assessed the quality of included studies using SYRCLE's tool. The outcome indicators consisted of at least one of the three key DPN endpoints (electrophysiology, behavioural assessment, and nerve structure) based on the Neurodiab guidelines. R 4.4.2 software was used to conduct all statistical analyses.

Results: 11 studies were identified, and the risk of bias in most studies was unclear generally. Pooled analyses demonstrated that exosome improved the nerve conduction velocity [MCV (SMD = 4.71 [2.18;7.25], P = 0.0003; I²= 91.8%), SCV (SMD = 1.07 [0.30;1.85], P = 0.0069; I²= 85.3%)], may restore IENFD [SMD = 1.46 [-0.85; 3.77], P = 0.2164; I²=88.7%], alleviated neuropathic pain [mechanical allodynia (SMD= -0.27 [-1.02;0.47], P = 0.4697; I² = 85.0%), thermal hyperalgesia (SMD= -1.48 [-2.45;-0.50], P = 0.003; I² = 88.4%)], ameliorated vascular function [blood flow perfusion in plantar (SMD = 2.84 [0.89; 4.80], P = 0.0043; I² = 74.9%), blood flow perfusion in sciatic nerves (SMD = 2.62 [0.80; 4.43], P = 0.0047; I² = 75.9%), vessel density (SMD = 2.69 [0.90; 4.49], P = 0.0032; I² = 0%)], and restored the peripheral nerve structure [sciatic nerve fiber diameter (SMD = 3.29 [1.61; 4.96], P = 0.0066; I² = 75.5%), axon diameter (SMD = 2.26 [1.64; 2.88], P < 0.0001; I² = 54.3%), myelin sheath thickness (SMD = 2.56 [1.39; 3.72], P < 0.0001; I² = 73.0%), g-ratio (SMD= -1.64 [-3.28; 0.00], P = 0.0502; I² = 34.17)]. Furthermore, after exosome therapy, the expressions of NF-200 (SMD = 2.57 [0.39; 4.75], P = 0.0210; I² = 33.0%), MBP (SMD = 2.27 [-1.49; 6.02], P = 0.1064; I² = 59.0%), and S-100β (SMD = 1.90 [0.09; 3.72], P = 0.0399; I² = 32.5%) evaluating axonal regeneration and remyelination increased significantly. Notably, high-glucose pretreatment of exosomes significantly attenuated these effects, while genetic overexpression modifications or novel dressings-mediated delivery partially counteracted this suppression.

Conclusions: Exosome therapy provides a novel therapeutic strategy for the benefit of neurovascular remodeling and functional recovery of DPN, especially when used in conjunction with exosome modification and novel dressings. To bridge the translational gap between preclinical and clinical studies, future research should conduct more large-scale, meticulously designed preclinical trials adhering to ARRIVE criteria before proceeding to clinical translation, to enhance translational rigor and mitigate risks associated with variability in study design.