[Development and antiviral activity of cepharanthine nanomicelles]

Cepharanthine (CEP) is a natural compound with broad-spectrum antiviral potential, while the extremely low aqueous solubility limits its in vivo applicability. This study aimed to develop CEP nanomicelles to enhance the solubility and bioavailability of CEP and evaluate their antiviral efficacy against coronavirus and other RNA virus models. Nanomicelles were constructed via a mixed surfactant system and characterized by dynamic light scattering, zeta potential analysis, and solubility measurements. The in vitro antiviral activity of the formulation was assessed via multiple coronavirus models, including GX_P2V, SARS-CoV-2 transcription and replication-competent virus-like particles (trVLPs), VSV pseudoviruses packaged with the spike protein of SARS-CoV-2, as well as other coronaviruses such as porcine epidemic diarrhea virus (PEDV) and swine acute diarrhea syndrome coronavirus (SADS-CoV). Furthermore, a golden hamster infection model was used to evaluate the in vivo antiviral efficacy and pharmacokinetic properties. The prepared CEP nanomicelles exhibited an average particle size of approximately 23 nm and the zeta potential of around -22 mV, with an increase of about 120 folds in solubility compared with free CEP. The formulation demonstrated potent antiviral activity across various coronavirus models, with EC₅₀ values ranging from 0.016 8 to 1.643 0 μmol/L, and maintained inhibitory effects against variant strains such as the Omicron sublineages, with the lowest EC₅₀ reaching 0.016 8 μmol/L. The animal experiment results revealed that CEP nanomicelles significantly reduced viral RNA levels in the lung tissue and achieved more stable plasma drug concentrations. Overall, CEP nanomicelles substantially improved the solubility and antiviral performance of CEP, exhibiting broad-spectrum efficacy, favorable safety, and tolerance to viral mutations, thus highlighting its potential as a promising candidate for broad-spectrum anti-coronavirus therapy.