Adenovirus (Ad) has been extensively developed as a gene delivery vector, but the potential side effect caused by systematic immunization remains one major obstacle for its clinical application. Needle-free mucosal immunization with Ad-based vaccine shows advantages but still faces poor mucosal responses. We herein report that the chemical engineering of single live viral-based vaccine effectively modulated the location and pattern of the subsequently elicited immunity. Through precisely assembly of functional materials onto single live Ad particle, the modified virus entered host cell in a phagocytosis-dependent manner, which is completely distinct from the receptor-mediated entry of native Ad. RNA-Seq data further demonstrated that the modified Ad-induced innate immunity was sharply reshaped via phagocytosis-related pathway, therefore promoting the activation and mature of antigen presentation cells (APC). Moreover, the functional shell enabled the modified Ad-based vector with enhanced muco-adhesion to nasal tissues in mice, and then prolonged resident time onto mucosal surface, leading to the robust mucosal IgA production and T cell immunity at local and even remote mucosal-associated lymphoid tissues. This study demonstrated that vaccine-induced immunity can be well modulated by chemistry engineering, and this method provides the rational design for needle-free mucosa-targeting vaccine against a variety of emerging infectious diseases.
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