Messenger RNA (mRNA) technology has already been successfully tested preclinically and there are ongoing clinical trials for protein replacement purposes; however, more effort has been put into the development of prevention strategies against infectious diseases. Apparently, mRNA vaccine approval against coronavirus disease 2019 (COVID-19) is a landmark for opening new opportunities for managing diverse health disorders based on this approach. Indeed, apart from infectious diseases, it has also been widely tested in numerous directions including cancer prevention and the treatment of inherited disorders. Interestingly, self-amplifying RNA (saRNA)-based technology is believed to display more developed RNA therapy compared with conventional mRNA technique in terms of its lower dosage requirements, relatively fewer side effects, and possessing long-lasting effects. Nevertheless, some challenges still exist that need to be overcome in order to achieve saRNA-based drug approval in clinics. Hence, the current review discusses the feasibility of saRNA utility for protein replacement therapy on various health disorders including rare hereditary diseases and also provides a detailed overview of saRNA advantages, its molecular structure, mechanism of action, and relevant delivery platforms.

Gaucher disease (GD), a rare hereditary lysosomal storage disorder, occurs due to a deficiency in the enzyme β-glucocerebrosidase (GCase). This deficiency leads to the buildup of substrate glucosylceramide (GlcCer) in macrophages, eventually resulting in various complications. Among its three types, GD2 is particularly severe with neurological involvements. Current treatments, such as enzyme replacement therapy (ERT), are not effective for GD2 and GD3 due to their inability to cross the blood-brain barrier (BBB). Other treatment approaches, such as gene or chaperone therapies are still in experimental stages. Additionally, GD treatments are costly and can have certain side effects. The successful use of messenger RNA (mRNA)-based vaccines for COVID-19 in 2020 has sparked interest in nucleic acid-based therapies. Remarkably, mRNA technology also offers a novel approach for protein replacement purposes. Additionally, self-amplifying RNA (saRNA) technology shows promise, potentially producing more protein at lower doses. This review aims to explore the potential of a cost-effective mRNA/saRNA-based approach for GD therapy. The use of GCase-mRNA/saRNA as a protein replacement therapy could offer a new and promising direction for improving the quality of life and extending the lifespan of individuals with GD.

Sialic acids (Sias) are a diverse family of nine-carbon backbone monosaccharides occupying terminal positions on cell surface and secreted glycans and are abundant at mucosal surfaces. Sias can be modified with O -acetyl esters on the side chain (C7 to C9) hydroxyls. Structural analysis and functional studies of these modifications are challenging due to chemical lability and variable resistance to sialidases. For in-depth analysis of the expression and functions of O -acetyl Sia modifications, we used a unique set of sialoglycan-recognizing probes, HPLC analysis of DMB-derivatized Sias and mice lacking the first known sialate O -acetyltransferase, CASD1. C7/C9- O -acetylated Sias are most abundant in the colon, with lower levels in the heart, brain, and spleen, and minimal levels in other digestive organs of wild-type mice. CASD1 deficiency led to a marked loss of C9/C7- O -acetylated Sias in the colon and other tissues. No differences were observed in colonic O -acetylated Sias from conventional and germ-free wild-type mice, indicating that Sia O -acetylation is independent of the commensal microbiota. Nonetheless, CASD1 deficiency caused subtle changes in microbial gene repertoire consistent with potential exploitation of Sias by subsets of intestinal microbes. Furthermore, CASD1-deficient mice exhibited more severe inflammation and ulceration upon colitis induction compared to controls. Reduced Sia O -acetylation was observed in mice during acute colitis and in colon biopsies from patients with inflammatory bowel disease. Together, our findings suggest CASD1 is the primary physiologically relevant enzyme to add C7/C8/C9- O -acetyl ester groups to Sias and that these Sia modifications exert important gut-protective functions, perhaps by preventing microbial Sia release and metabolism.

Glycoengineering of IgG, particularly Fc glycosylation, holds significant promise for treating autoimmune diseases by modulating antibody effector functions. However, methods that precisely control IgG glycosylation profiles in vivo are still lacking. In this study, by delivering mRNAs encoding the glycosyltransferases B4GALT1 and ST6GAL1 intravenously, we successfully expressed functional enzymes and demonstrated therapeutic benefits in rheumatoid arthritis animal models in a platelet-dependent manner. We further verified that intra-articular administration effectively ameliorated collagen-induced arthritis in rats. Our findings demonstrate that IgG galactosylation and sialylation, modulated by mRNA drug technology, shift immune responses from pro-inflammatory to anti-inflammatory states, similar to the mechanisms of intravenous immunoglobulin (IVIG) therapies. This study establishes glycosyltransferase-encoding mRNA-LNP technology as a versatile platform for modulating in vivo IgG glycosylation and treating associated diseases.

CD47 inhibitors have emerged as promising candidates in cancer immunotherapy by activating macrophage phagocytosis through CD47/SIRPα signal blockade and enhancing dendritic cell antigen presentation. However, their clinical efficacy remains limited and is accompanied by severe side effects, including anemia and hemagglutination. To address these limitations, a localized delivery strategy is developed using lipid nanoparticles to encapsulate mRNA encoding a secreted CD47 inhibitor. This mRNA‐derived CD47 inhibitor effectively activated macrophages against cancer cells in vitro. To improve its modest tumor‐suppressive effects in vivo, a combination therapy is formulated by co‐delivering mRNAs encoding the CD47 inhibitor and a cytokine cocktail (interleukins 12, 15, and 21), achieving synergistic antitumor effects. Notably, this strategy induces robust systemic antitumor immunity and long‐lasting immunological memory, effectively suppressing metastatic tumor progression following localized treatment of the primary tumor. Mechanistically, the mRNA‐derived CD47 inhibitor promoted the differentiation of conventional type 1 dendritic cells, facilitating T cell cross‐priming and activating cytotoxic T cells. Additionally, the cytokine cocktail further augmented the antitumor activity of these cytotoxic T cells. These findings present a promising strategy for advancing clinical cancer treatment, addressing key challenges associated with current CD47 inhibitor therapies.

Sialic acids are terminal monosaccharides that cap glycans on glycoconjugates. Accumulating clinical and experimental evidence shows that obesity, insulin resistance, and diabetes are accompanied by changes in sialic-acid levels. In these conditions, the sialic-acid axis is also broadly remodeled: writers (sialyltransferases), erasers (neuraminidases), and readers (Siglecs) are dysregulated across adipose tissue, liver, pancreas, endothelium, and blood, shifting insulin signaling and inflammatory tone. This review summarizes relevant studies from the perspectives of disease clinical indicators, molecular mechanisms, and interventions targeting sialic acid. Taken together, these results confirm that sialic acids and related molecules play important roles in multiple metabolic diseases; however, controversies remain due to differences in glycan structure, isoforms, and tissue specificity, particularly regarding the precise roles of neuraminidases. Future studies should build on advanced, standardized glycomic and glycoproteomic measures to define molecule- and tissue-specific roles of sialic acids in metabolic disease, enabling reliable biomarkers and guiding targeted therapy.