Mucosal tissue constitutes the largest interface between the body and the external environment, regulating the entry of pathogens, particles, and molecules. Mucosal immunization is the most effective way to trigger a protective mucosal immune response. However, the majority of the currently licensed vaccines are recommended to be administered by intramuscular injection, which has obvious shortcomings, such as high production costs, low patient compliance, and lack of mucosal immune response. Strategies for eliciting mucosal and systemic immune responses are being developed, including appropriate vaccine adjuvant, delivery system, and bacterial or viral vectors. Biodegradable mucoadhesive nanoparticles (NPs) are the most promising candidate for vaccine delivery systems due to their inherent immune adjuvant property and the ability to protect the antigen from degradation, sustain the release of loaded antigen, and increase the residence time of antigen at the administration site. The current review outlined the complex structure of mucosa, the mechanism of interaction between NPs and mucosa, factors affecting the mucoadhesion of NPs, and the application of the delivery system based on mucoadhesive NPs in the field of vaccines. Moreover, this review demonstrated that the biodegradable and mucoadhesive NP-based delivery system has the potential for mucosal administration of vaccines. Graphical Abstract:

Gasdermin D (GSDMD) participates in the activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.

Recently, GSDMD has been reported as a key executioner for pyroptosis. This study first demonstrates the molecular mechanism of pGSDMD-mediated pyroptosis and that the pGSDMD-mediated pyroptosis protects host cells against PEDV infection.

The present study was to investigate the molecular mechanisms underlying macrophage inflammatory response to polysaccharides from Peucedanum praeruptorum Dunn (PPDs) and elucidate the receptors and signaling pathways associated with PPDs-mediated macrophage activation. MTT and Griess method were performed to investigate the effects of PPDs on cell viability and NO production. Neutral red and FITC-dextran were used to determine the pinocytic and phagocytic activity. RT-qPCR and ELISA were employed to analyze the mRNA expression of inflammatory factors and production of cytokines and chemokines. RNA-seq and bioinformatics analysis were conducted to determine the underlying molecules, regulators and pathways, which were further validated by pathway inhibition and neutralization assays. The results indicated that PPDs significantly enhanced pinocytic and phagocytic activity, promoted the expression and secretion of inflammatory factors and chemokines, and boosted the expression of accessory and costimulatory molecules. RNA-Seq analysis identified 1343 DEGs, 405 GO terms and 91 KEGG pathways. IL6 and TNF were identified as hubs of connectivity in PPDs-mediated macrophage activation. "Cytokine-cytokine receptor interaction", "TNF signaling pathway", "NF-kappa B signaling pathway", "JAK-STAT signaling pathway" and "MAPK signaling pathway" were the most significant pathways. The pathway inhibition assay revealed that MAPK and NF-κB pathways were essential to macrophage activation by PPDs. TLR2 and TLR4 were uncovered to be the functional receptors and involved in recognition of PPDs. These results indicated that PPDs modulated macrophage inflammatory response mainly through TLR2/TLR4-dependent MAPK and NF-κB pathways.