Abstract Background and Aims Evidence suggests that interferon alpha (IFNα) plays an essential role in decreasing the HBsAg quantification and elevating the rate of clinical cure in chronic hepatitis B (CHB). However, the mechanisms underlying the effects of the exosomes on the expression of host genes in IFNα treatment remain unclear. Methods CHB patients with IFNα treatment were divided into responders and non‐responders according to the degree of HBsAg decline. Through microRNA sequencing and a series of molecular biology methods, the key microRNAs in serum exosomes associated with clinical antiviral response of Peg‐IFNα treatment in nucleotide analogue‐treated CHB patients were investigated. The roles of exosomal miRNAs on the IFNα signal pathway were explored in macrophages. Results MicroRNA sequencing and RT‐qPCR assays confirmed six distinctly declined miRNAs in serum exosomes of responders at week 12 compared with levels at baseline. Exosomes with declined miR27b‐3p in the serum of Peg‐IFNα‐treated responders activated phosphorylation of interferon regulatory factor 3/7 (IRF3/7) in IFNα synthesis pathway in macrophages. However, miR27b‐3p overexpression in HepAD38 cells suppressed IFNα synthesis in macrophages, resulting in insufficient ability to eliminate HBV, whereas the inhibitory effect could be blocked by inhibitors of exosomes release. Luciferase assay showed miR‐27b‐3p directly suppressed retinoic acid‐inducible gene I (RIG‐I) and TANK‐binding kinase 1 (TBK1) expressions, and these effects could be abrogated in mutation experiments. Conclusions In IFNα treatment, exosomes with declined miR‐27b‐3p triggered activation of RIG‐I/TBK1 signalling in macrophages against HBV. Serum exosomal miR‐27‐3p might represent a potential biomarker for patients with CHB.
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