Exosomal miR-223-3p, associated with NLRP3-related neuroinflammation, as a potential biomarker for mild cognitive impairment in patients with type 2 diabetes mellitus

Background Neuroinflammation has been implicated in diabetic cognitive dysfunction, with the NLRP3 playing an important role. Objective This study aimed to elucidate the regulatory role of miR-223-3p in NLRP3 associated neuroinflammation and its potential as a biomarker for mild cognitive impairment (MCI) in type 2 diabetes mellitus (T2DM). Methods Diabetic mouse models were generated by 24 weeks of high-fat diet feeding, with cognitive impairment verified by behavioral assessments. Hippocampal tissues were analyzed by microRNA sequencing and validated for miR-223-3p expression. NLRP3-mediated neuroinflammation was examined in vivo, while in vitro assays using BV2 cells assessed mechanistic pathways. BV2 cells with miR-223-3p knockdown and overexpression to evaluate its effects on NLRP3. Clinically, plasma exosomal miR-223-3p was quantified in T2DM patients with and without MCI and correlated with neuropsychological test scores. Results Diabetic mice exhibited cognitive decline, reduced hippocampal miR-223-3p, microglial activation, and elevated NLRP3 and pro-inflammatory cytokines. miR-223-3p knockdown and overexpression induced and attenuated neuroinflammation, respectively. Luciferase reporter gene assays confirmed the direct regulatory of miR-223-3p on NLRP3. Clinically, exosomal miR-223-3p levels were significantly lower in T2DM patients with MCI (n = 98) compared with cognitive normal patients (n = 147), correlating with global cognition, and immediate memory performance. ROC analysis demonstrated that, when using the threshold of 0.7565, miR-223-3p achieved a diagnostic specificity of 71.4% and a sensitivity of 68.7% for identifying MCI. Conclusions miR-223-3p exerts neuroprotective effects by suppressing NLRP3-mediated neuroinflammation. Its downregulation contributes to cognitive impairment in diabetes, and circulating exosomal miR-223-3p represents a potential biomarker for identifying MCI in T2DM.