In its own right, vaccinology has been undergoing a revolution, and there are now a large number of innovative projects seeking to develop both prophylactic and therapeutic vaccines against diseases such as Hepatitis B, influenza, HIV, and cancers. [4-6] Generally speaking, the major advantages conferred by nanovaccines include improving stability by protecting antigens from premature degradation, providing good adjuvant properties, and assisting in the targeted delivery of an antigen to antigen-presenting cells (APCs). [7] A large variety of nanoscale materials have been deployed in nanovaccine designs. Seminal work with inorganic nanoparticles (NPs, e.g., gold, carbon, and silica) established the capacity of nanovaccine-bound antigens to elicit desired immune responses. Subsequent technologies have elaborated beyond inorganic NPs, for example, use of inorganic/ organic hybrid NPs (e.g., PEI adopted silica NPs and biomimetic magnetosomes) to enhance antigen immunogenicity. [8,9] Recently, new types of organic NPs (e.g., lipoprotein-mimicking nanodisks, pickering emulsions, and nanogels) have also received great attention for their applications in vaccines. [10-16] Recent years have seen enormous advances in nanovaccines for both prophylactic and therapeutic applications, but most of these technologies employ chemical or hybrid semi-biosynthetic production methods. Thus, production of nanovaccines has to date failed to exploit biology-only processes like complex sequential post-translational biochemical modifications and scalability, limiting the realization of the initial promise for offering major performance advantages and improved therapeutic outcomes over conventional vaccines. A Nano-B5 platform for in vivo production of fully protein-based, self-assembling, stable nanovaccines bearing diverse antigens including peptides and polysaccharides is presented here. Combined with the self-assembly capacities of pentamer domains from the bacterial AB 5 toxin and unnatural trimer peptides, diverse nanovaccine structures can be produced in common Escherichia coli strains and in attenuated pathogenic strains. Notably, the chassis of these nanovaccines functions as an immunostimulant. After showing excellent lymph node targeting and immunoresponse elicitation and safety performance in both mouse and monkey models, the strong prophylactic effects of these nanovaccines against infection, as well as their efficient therapeutic effects against tumors are further demonstrated. Thus, the Nano-B5 platform can efficiently combine diverse modular components and antigen cargos to efficiently generate a potentially very large diversity of nanovaccine structures using many bacterial species.
