Nasal vaccines: solutions for respiratory infectious diseases.

Nasal vaccines induce pathogen-specific dual protective immunity at mucosal surfaces and systemically throughout the body. Consequently, nasal vaccines both prevent pathogen invasion and reduce disease severity. Because of these features, nasal vaccines are considered to be a next-generation tool for preventing respiratory infectious diseases, including COVID-19. However, nasal vaccines must overcome key safety concerns given the anatomic proximity of the central nervous system (CNS) via the olfactory bulbs which lie next to the nasal cavity. This review summarizes current efforts to develop safe and effective nasal vaccines and delivery systems, as well as their clinical applications for the prevention of respiratory infections. We also discuss various concerns regarding the safety of nasal vaccines and introduce a system for evaluating them.

A novel inhalable quercetin-alginate nanogel as a promising therapy for acute lung injury.

BACKGROUND: Acute lung injury (ALI), a severe health-threatening disease, has a risk of causing chronic pulmonary fibrosis. Informative and powerful evidence suggests that inflammation and oxidative stress play a central role in the pathogenesis of ALI. Quercetin is well recognized for its excellent antioxidant and anti-inflammatory properties, which showed great potential for ALI treatment. However, the application of quercetin is often hindered by its low solubility and bioavailability. Therefore, to overcome these challenges, an inhalable quercetin-alginate nanogel (QU-Nanogel) was fabricated, and by this special "material-drug" structure, the solubility and bioavailability of quercetin were significantly enhanced, which could further increase the activity of quercetin and provide a promising therapy for ALI. RESULTS: QU-Nanogel is a novel alginate and quercetin based "material-drug" structural inhalable nanogel, in which quercetin was stabilized by hydrogen bonding to obtain a "co-construct" water-soluble nanogel system, showing antioxidant and anti-inflammatory properties. QU-Nanogel has an even distribution in size of less than 100 nm and good biocompatibility, which shows a stronger protective and antioxidant effect in vitro. Tissue distribution results provided evidence that the QU-Nanogel by ultrasonic aerosol inhalation is a feasible approach to targeted pulmonary drug delivery. Moreover, QU-Nanogel was remarkably reversed ALI rats by relieving oxidative stress damage and acting the down-regulation effects of mRNA and protein expression of inflammation cytokines via ultrasonic aerosol inhalation administration. CONCLUSIONS: In the ALI rat model, this novel nanogel showed an excellent therapeutic effect by ultrasonic aerosol inhalation administration by protecting and reducing pulmonary inflammation, thereby preventing subsequent pulmonary fibrosis. This work demonstrates that this inhalable QU-Nanogel may function as a promising drug delivery strategy in treating ALI.

Co-Delivery of mRNA and pDNA Using Thermally Stabilized Coacervate-Based Core-Shell Nanosystems.

Co-delivery of different species of protein-encoding polynucleotides, e.g., messenger RNA (mRNA) and plasmid DNA (pDNA), using the same nanocarrier is an interesting topic that remains scarcely researched in the field of nucleic acid delivery. The current study hence aims to explore the possibility of the simultaneous delivery of mRNA (mCherry) and pDNA (pAmCyan) using a single nanocarrier. The latter is based on gelatin type A, a biocompatible, and biodegradable biopolymer of broad pharmaceutical application. A core-shell nanostructure is designed with a thermally stabilized gelatin-pDNA coacervate in its center. Thermal stabilization enhances the core's colloidal stability and pDNA shielding effect against nucleases as confirmed by nanoparticle tracking analysis and gel electrophoresis, respectively. The stabilized, pDNA-loaded core is coated with the cationic peptide protamine sulfate to enable additional surface-loading with mRNA. The dual-loaded core-shell system transfects murine dendritic cell line DC2.4 with both fluorescent reporter mRNA and pDNA simultaneously, showing a transfection efficiency of 61.4 ± 21.6% for mRNA and 37.6 ± 19.45% for pDNA, 48 h post-treatment, whereas established commercial, experimental, and clinical transfection reagents fail. Hence, the unique co-transfectional capacity and the negligible cytotoxicity of the reported system may hold prospects for vaccination among other downstream applications.

Severe Acute Respiratory Syndrome Coronavirus-2 Spike Protein Nanogel as a Pro-Antigen Strategy with Enhanced Protective Immune Responses.

Prevention and intervention methods are urgently needed to curb the global pandemic of coronavirus disease-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Herein, a general pro-antigen strategy for subunit vaccine development based on the reversibly formulated receptor binding domain of SARS-CoV-2 spike protein (S-RBD) is reported. Since the poor lymph node targeting and uptake of S-RBD by antigen-presenting cells prevent effective immune responses, S-RBD protein is formulated into a reversible nanogel (S-RBD-NG), which serves as a pro-antigen with enhanced lymph node targeting and dendritic cell and macrophage accumulation. Synchronized release of S-RBD monomers from the internalized S-RBD-NG pro-antigen triggers more potent immune responses in vivo. In addition, by optimizing the adjuvant used, the potency of S-RBD-NG is further improved, which may provide a generally applicable, safer, and more effective strategy for subunit vaccine development against SARS-CoV-2 as well as other viruses.