The highly immunosuppressive tumor microenvironment (TME) in solid tumors often dampens the efficacy of immunotherapy. In this study, bacterial outer membrane vesicles (OMVs) are demonstrated as powerful immunostimulants for TME reprogramming. To overcome the obstacles of antibody‐dependent clearance and high toxicity induced by OMVs upon intravenous injection (a classic clinically relevant delivery mode), calcium phosphate (CaP) shells are employed to cover the surface of OMVs, which enables potent OMV‐based TME reprograming without side effects. Meanwhile, the pH‐sensitive CaP shells facilitate the neutralization of acidic TME, leading to highly beneficial M2‐to‐M1 polarization of macrophages for improved antitumor effect. Moreover, the outer shells can be integrated with functional components like folic acid or photosensitizer agents, which facilitates the use of the OMV‐based platform in combination therapies for a synergic therapeutic effect.

Macrophage-tumor chimeric exosomes inhibit tumor growth in multiple mouse models by stimulating the immune response and tumor microenvironment.

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.

Therapeutic cancer vaccines that harness the immune system to reject cancer cells have shown great promise for cancer treatment. Although a wave of efforts have spurred to improve the therapeutic effect, unfavorable immunization microenvironment along with a complicated preparation process and frequent vaccinations substantially compromise the performance. Here, we report a novel microcapsule-based formulation for high-performance cancer vaccinations. The special self-healing feature provides a mild and efficient paradigm for antigen microencapsulation. After vaccination, these microcapsules create a favorable immunization microenvironment in situ, wherein antigen release kinetics, recruited cell behavior, and acid surrounding work in a synergetic manner. In this case, we can effectively increase the antigen utilization, improve the antigen presentation, and activate antigen presenting cells. As a result, effective T cell response, potent tumor inhibition, antimetastatic effects, and prevention of postsurgical recurrence are achieved with various types of antigens, while neoantigen was encapsuled and evaluated in different tumor models.