Antiviral efficacy of LNP-delivered IFN-α14-ApoAI mRNA for chronic hepatitis B.

Chronic hepatitis B virus (HBV) infection remains a major global health burden, and current therapeutic options such as pegylated interferon-α (PEG-IFNα) yield limited clinical efficacy. Here, we developed a lipid nanoparticle (LNP) formulation encapsulating mRNA encoding an IFN-α14-ApoAI fusion protein and evaluated its anti-HBV activity and safety profile in humanized IFNAR mouse models. First, adeno-associated virus (AAV)-mediated delivery of IFN-α14-ApoAI provided preliminary evidence of safe and sustained HBV suppression in mice, suggesting the feasibility of gene delivery of this fusion protein for anti-HBV therapy. On this basis, we formulated IFN-α14-ApoAI mRNA into SM-102-based LNPs, designated as IFN-α14 LNP. A single intravenous injection of this LNP formulation showed a trend toward dose-dependent reduction of HBV antigens. Furthermore, a single intravenous dose of 4 μg IFN-α14 LNP showed comparable inhibition of HBV antigens to the clinically approved drug PEG-IFNα2 (2 μg, subcutaneously). Moreover, safety assessment showed that the 4 μg dose was well tolerated with no detectable organ toxicity, only transient and self-limited cytokine elevations, and reversible splenic immune activation. In addition, repeated dosing of IFN-α14 LNP in mice induced neutralizing antibodies against the xenogeneic human IFN-α14, a limitation that is not anticipated in humans due to immune tolerance to self-proteins. Collectively, our findings demonstrate that IFN-α14 LNP exerts anti-HBV activity while exhibiting a favorable safety profile in humanized IFNAR mouse models. It represents a novel therapeutic candidate for chronic hepatitis B that still requires refinement.