Lactoferricin enables adenovirus infection of human skeletal muscle cells.

Although adenoviruses (AdVs) possess advantageous features as vectors, several challenges remain. These include a high prevalence of neutralizing antibodies against certain AdV types and the inability to efficiently transduce CAR-deficient cells and tissues. We showed previously that lactoferricin (Lfcin) enhances CAR-independent HAdV-C5 infection of epithelial and T-cells. Here, we assessed the ability of Lfcin to enable HAdV-C5 infection and transduction of human skeletal muscle cells. Lfcin increases HAdV-C5 infection and transduction of muscle myoblasts and myotubes by 10- to 30-fold. Enhanced infection correlates with increased cell binding, which differs mechanistically from that of coagulation factor X-mediated binding, as it remains unaffected by the removal of heparan sulfate. Additionally, Lfcin reduces the neutralizing effects of serum against HAdV-C5, suggesting it may shield key epitopes. By enabling viral binding to muscle cells and mitigating serum neutralization, Lfcin offers a novel strategy to improve the efficiency and durability of HAdV-C5-based gene delivery systems.