Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance.

Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.

Inhalable exosomes outperform liposomes as mRNA and protein drug carriers to the lung.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, coupled with the ongoing coronavirus disease 2019 (COVID-19) pandemic. mRNA lipid nanoparticle (LNP) vaccines have been developed, but their intramuscular delivery limits pulmonary bioavailability. Inhalation of nanoparticle therapeutics offers localized drug delivery that minimizes off targeted adverse effects and has greater patient compliance. However, LNP platforms require extensive reformulation for inhaled delivery. Lung-derived extracellular vesicles (Lung-Exo) offer a biological nanoparticle alternative that is naturally optimized for mRNA translation and delivery to pulmonary cells. We compared the biodistribution of Lung-Exo against commercially standard biological extracellular vesicles (HEK-Exo) and LNPs (Lipo), where Lung-Exo exhibited superior mRNA and protein cargo distribution to and retention in the bronchioles and parenchyma following nebulization administration. This suggests that inhaled Lung-Exo can deliver mRNA and protein drugs with enhanced pulmonary bioavailability and therapeutic efficacy.

Inhalable dry powder mRNA vaccines based on extracellular vesicles.

Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.

Pluripotent Stem Cells: Cancer Study, Therapy, and Vaccination.

INTRODUCTION: Pluripotent stem cells (PSCs) are promising tools for modern regenerative medicine applications because of their stemness properties, which include unlimited self-renewal and the ability to differentiate into all cell types in the body. Evidence suggests that a rare population of cells within a tumor, termed cancer stem cells (CSCs), exhibit stemness and phenotypic plasticity properties that are primarily responsible for resistance to chemotherapy, radiotherapy, metastasis, cancer development, and tumor relapse. Different therapeutic approaches that target CSCs have been developed for tumor eradication. RESULTS AND DISCUSSION: In this review, we first provide an overview of different viewpoints about the origin of CSCs. Particular attention has been paid to views believe that CSCs are probably appeared through dysregulation of very small embryonic-like stem cells (VSELs) which reside in various tissues as the main candidate for tissue-specific stem cells. The expression of pluripotency markers in these two types of cells can strengthen the validity of this theory. In this regard, we discuss the common properties of CSCs and PSCs, and highlight the potential of PSCs in cancer studies, therapeutic applications, as well as educating the immune system against CSCs. CONCLUSION: In conclusion, the resemblance of CSCs to PSCs can provide an appropriate source of CSC-specific antigens through cultivation of PSCs which brings to light promising ideas for prophylactic and therapeutic cancer vaccine development.