摘要
Current attempts in vaccine delivery systems concentrate on replicating the natural dissemination of live pathogens,but neglect that pathogens evolve to evade the immune system rather than to provoke it.In the case of enveloped RNA viruses,it is the natural dissemination of nucleocapsid protein(NP,core antigen)and surface antigen that delays NP exposure to immune surveillance.Here,we report a multi-layered aluminum hydroxide-stabilized emulsion(MASE)to dictate the delivery sequence of the antigens.In this manner,the receptor-binding domain(RBD,surface antigen)of the spike protein was trapped inside the nanocavity,while NP was absorbed on the outside of the droplets,enabling the burst release of NP before RBD.Compared with the natural packaging strategy,the inside-out strategy induced potent type I interferon-mediated innate immune responses and triggered an immune-potentiated environment in advance,which subsequently boosted CD40+DC activations and the engagement of the lymph nodes.In both H1N1 influenza and SARS-CoV-2 vaccines,rMASE significantly increased antigen-specific antibody secretion,memory T cell engagement,and Th1-biased immune response,which diminished viral loads after lethal challenge.By simply reversing the delivery sequence of the surface antigen and core antigen,the inside-out strategy may offer major implications for enhanced vaccinations against the enveloped RNA virus.
基金
supported by the National Key Research and Development Program of China(2021YFE020527,2021YFC2302605,2021YFC2300142),"From 0 to 1"Original Innovation Project of Basic Frontier Scientific Research Program of Chinese Academy of Sciences(ZDBS-LY-SLH040)
Bejing Nova Program(Z201100006820139)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(Grant No.21821005)
CAS Project for Young Scientists in Basic Research(YSBR-010)
the Pilot Project of Chinese Academy of Sciences(Grant No.XDB29040303)
The National Natural Science Fund for Outstanding Young Scholar(T2222022)
National Natural Science Foundation of China(Grant No.32030062),Youth Innovation Promotion Association of the Chinese Academy of Sciences(NO.2020000053)
the foundation of Innovation Academy for Green Manufacture Institute,Chinese Academy of Sciences(Grand No.IAGM2020C30).
