Radioprotection of healthy tissue via nanoparticle-delivered mRNA encoding for a damage-suppressor protein found in tardigrades
Related Articles
Functionality and translation fidelity characterization of mRNA vaccines using platform based mass spectrometry detection
The success of mRNA-based therapeutics and vaccines is attributed to their rapid development, adaptability, and scalable production. Modified ribonucleotides like N1-methylpseudouridine enhance stability and reduce immunogenicity but were recently found to induce cellular immunity to off-target, +1 ribosomal frameshifted protein. We developed a new platform using cell-free translation (CFT) and liquid chromatography-tandem mass spectrometry (MS) to detect, characterize, and quantify antigen proteins from mRNA constructs. This workflow enabled evaluation of mRNA functionality under thermal stress and assessment of multivalent formulations with high sequence homology. The MS approach was further applied following cell-based translation and demonstrated high sensitivity and specificity, accurately identifying all six translated proteins and their relative abundances from a hexavalent mRNA drug product in a dose-dependent manner. Furthermore, the CFT-MS approach successfully identified +1 ribosomal frameshifting linked to N1-methylpseudouridylation. This methodology provides a valuable analytical tool for assessing mRNA quality and functionality in vaccine development and beyond.
A capless hairpin-protected mRNA vaccine encoding the full-length Influenza A hemagglutinin protects mice against a lethal Influenza A infection
The success of mRNA vaccines in controlling the COVID 19 pandemic has confirmed the efficacy of synthetically synthesized mRNA in humans and has also provided a blueprint on how to design them in terms of molecular structure and cost. We describe a mRNA vector that, unlike linear mRNAs used in current vaccines/therapeutics, does not require a 5′ cap to function. The described mRNA vector initiates translation from an internal ribosomal entry site (IRES) and contains specially designed self-folding secondary structures (hairpins) to protect the 5′ end against degradation, dramatically improving its stability. The produced mRNA did not require any additional modifications for functionality. The 5′ hairpins completely inhibited cap-dependent translation, and all vectors containing them required an IRES to express protein. When this capless mRNA vector was constructed to express the full-length Influenza A membrane protein hemagglutinin (HA), complexed with pre-formed lipid-based nanoparticles, and then injected into mice as a vaccine, it generated high titers of anti-HA antibodies and protected mice against a lethal dose of Influenza A.
Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.
The biomechanics of the vagina: a complete review of incomplete data
The biomechanical properties of the vagina are crucial to fulfilling physiological functions such as menstruation, sexual intercourse, pregnancy, and childbirth. Alterations to these properties are associated with pathological conditions that profoundly affect women. This review provides a comprehensive synthesis of the limited and inconsistent data on the biomechanics al properties of the vagina as they relate to pregnancy, parity, prolapse, and menopause, guiding new research efforts that advance women’s health.
Optimizing rabies mRNA vaccine efficacy via RABV-G structural domain screening and heterologous prime-boost immunization
mRNA vaccine has become a promising technology platform for rabies prevention. This study explores the roles of different structural domains of rabies virus glycoprotein (RABV-G) and heterologous prime-boost strategies for enhanced immune responses and protection. The results suggested that mRNA vaccines encoding full-length RABV-G (RABV-Full) and RABV-R333Q induced strong immune responses and provided full protection against rabies, while mRNA vaccines encoding ectodomain/transmembrane domain (RABV-TE) and ectodomain (RABV-E) were less effective. Heterologous immunization results revealed that mRNA-primed strategies yielded higher long-lasting VNTs, but lower early VNTs than inactivated rabies virus (IRV)-primed strategies. 2×RABV-Full and IRV > RABV-Full provided 100% protection, while that of RABV-Full>IRV was 90%. Transcriptome analysis showed that rabies mRNA vaccine induced both MHCI and MHCII antigen presentation, as well as B/T cell activation. In conclusion, full-length RABV-G mRNA vaccines, particularly with an ‘IRV prime and RABV-Full boost’ strategy, hold great potential for rabies prevention.
Responses