Rabies, a persistent and historic global zoonosis, continues to impose a significant public health burden, particularly in resource-limited regions. The causative agent, rabies virus (RABV; genus Lyssavirus, family Rhabdoviridae), possesses a surface glycoprotein (G) that is pivotal for virus entry and pathogenesis. Rabies virus glycoprotein (RABV-G) mediates binding to host cell receptor(s) and acidic-pH-dependent membrane fusion, enabling the release of RNA genome into the host cytoplasm. It is also the main target for neutralizing antibodies and the major component of rabies vaccines. In this review, we systematically summarize the structural features, functional mechanisms, and antiviral targeting strategies of RABV-G, emphasizing recent structural insights into its conformational dynamics. Key neutralizing epitopes and their recognition by monoclonal antibodies are discussed, along with antiviral strategies, including entry inhibitors, antibody therapies, and advanced vaccine platforms. Accumulating structural analyses indicate that the pH-dependent and reversible conformational transitions of this class Ⅲ viral fusion protein underlie both viral infectivity and vulnerability to immune intervention. Collectively, available data establish that neutralizing epitopes on RABV-G are conformationally defined and dynamically regulated during fusion, thereby constraining viral entry and dictating the effectiveness of antibody- and entry inhibitor–mediated neutralization. Together, these findings establish RABV-G as the primary determinant of rabies virus virulence and immune control. By exploring the structural framework and prospective treatment modalities, we aim to enhance our understanding of rabies virus, particularly the glycoprotein G, and support ongoing initiatives to alleviate the burden of rabies, offering renewed optimism in the battle against this formidable infectious disease.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has decreased the efficacy of SARS-CoV-2 vaccines in containing coronavirus disease 2019 (COVID-19) over time, and booster vaccination strategies are urgently necessitated to achieve sufficient protection. Intranasal immunization can improve mucosal immunity, offering protection against the infection and sustaining the spread of SARS-CoV-2. In this study, an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum, nasal lavage fluid, and bronchoalveolar lavage fluid compared with only two doses of mRNA vaccine. After intranasal boosting with the RBD-HR vaccine, the levels of serum neutralizing antibodies against prototype and variant strains of SARS-CoV-2 pseudoviruses were markedly higher than those in mice receiving mRNA vaccine alone, and intranasal boosting with the RBD-HR vaccine also inhibited the binding of RBD to hACE2 receptors. Furthermore, the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103⁺ dendritic cells in the respiratory mucosa, and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs, including mediastinal lymph nodes, inguinal lymph nodes, and spleen. Collectively, these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locally and systemically.