Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals 1,2 . Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis 3 , and thus, alternative therapeutic approaches are urgently needed 2,3 . Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multi-drug resistant (MDR) bacteria-induced sepsis in mice with immunosuppression. The MACs are constructed by transfection of vitamin C lipid nanoparticles (V C LNPs) that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA.

mRNA vaccines have become a versatile technology for the prevention of infectious diseases and the treatment of cancers. In the vaccination process, mRNA formulation and delivery strategies facilitate effective expression and presentation of antigens, and immune stimulation. mRNA vaccines have been delivered in various formats: encapsulation by delivery carriers, such as lipid nanoparticles, polymers, peptides, free mRNA in solution, and ex vivo through dendritic cells. Appropriate delivery materials and formulation methods often boost the vaccine efficacy which is also influenced by the selection of a proper administration route. Co-delivery of multiple mRNAs enables synergistic effects and further enhances immunity in some cases. In this chapter, we overview the recent progress and existing challenges in the formulation and delivery technologies of mRNA vaccines with perspectives for future development.

No abstract

SARS-CoV-2 vaccines based on inactivated live virus, recombinant viral vector, mRNA, DNA, and recombinant protein are currently in clinical trials. [6] Among these agents, an mRNA-based vaccine candidate quickly entered the clinical trial, because of the fast process for developing and manufacturing mRNA. [7] In order to express an antigen effectively, an mRNA requires several essential components, including 5′ cap, 5′ untranslated region (5′ UTR), antigen-encoding sequence, 3′ untranslated region (3′ UTR), and the poly adenylated tail. [8] Among these components, the 5′ UTR and 3′ UTR are unique regulators for protein translation. [9] The design and selection of 5′ UTR and 3′ UTR are critically important to ensure the sufficient production of antigens and efficacious vaccination. [10]

Messenger RNA (mRNA) therapeutics have been explored to treat various genetic disorders. Lipid-derived nanomaterials are currently one of the most promising biomaterials that mediate effective mRNA delivery. However, efficiency and safety of this nanomaterial-based mRNA delivery remains a challenge for clinical applications. Here, we constructed a series of lipid-like nanomaterials (LLNs), named functionalized TT derivatives (FTT), for mRNA-based therapeutic applications in vivo. After screenings on the materials, we identified FTT5 as a lead material for efficient delivery of long mRNAs, such as human factor VIII (hFVIII) mRNA (~4.5 kb) for expression of hFVIII protein in hemophilia A mice. Moreover, FTT5 LLNs demonstrated high percentage of base editing on PCSK9 in vivo at a low dose of base editor mRNA (~5.5 kb) and single guide RNA. Consequently, FTT nanomaterials merit further development for mRNA-based therapy.