NFAT and NF-κB dynamically co-regulate TCR and CAR signaling responses in human T cells.

While it has been established that the responses of T cells to antigens are combinatorially regulated by multiple signaling pathways, it remains elusive what mechanisms cells utilize to quantitatively modulate T cell responses during pathway integration. Here, we show that two key pathways in T cell signaling, calcium/nuclear factor of activated T cells (NFAT) and protein kinase C (PKC)/nuclear factor κB (NF-κB), integrate through a dynamic and combinatorial strategy to fine-tune T cell response genes. At the cis-regulatory level, the two pathways integrate through co-binding of NFAT and NF-κB to immune response genes. Pathway integration is further regulated temporally, where T cell receptor (TCR) and chimeric antigen receptor (CAR) activation signals modulate the temporal relationships between the nuclear localization dynamics of NFAT and NF-κB. Such physical and temporal integrations together contribute to distinct modes of expression modulation for genes. Thus, the temporal relationships between regulators can be modulated to affect their co-targets during immune responses, underscoring the importance of dynamic combinatorial regulation in cellular signaling.

Multifunctional Milk-Derived Small Extracellular Vesicles and Their Biomedical Applications.

In recent years, small extracellular vesicles (sEVs) have been regarded as the next generation of novel delivery systems after lipid nanoparticles because of their advantages and huge prospects in drug delivery. Studies have shown that sEVs are abundant in milk and therefore can be a large and economical source of sEVs. Natural milk-derived small extracellular vesicles (msEVs) have important functions such as immune regulation, anti-bacterial infection, anti-oxidative, etc., and play a beneficial role in human health at multiple levels, including intestinal health, bone/muscle metabolism, and microbiota regulation. In addition, because they can pass the gastrointestinal barrier and have low immunogenicity, good biocompatibility, and stability, msEVs are considered a crucial oral drug delivery vehicle. Moreover, msEVs can be further engineered for targeted delivery to prolong the circulation time or enhance local drug concentrations. However, msEVs separation and purification, complex contents, and quality control hinder their application in drug delivery. This paper provides a comprehensive review of the biogenesis and characteristics, isolation and purification, composition, loading methods, and function of msEVs, based on which their applications in biomedical fields are further explored.

Exosomal ncRNAs: The pivotal players in diabetic wound healing.

Diabetes is the most prevalent metabolic disease in the world today. In addition to elevated blood glucose, it also causes serious complications, which has a significant effect on the quality of life of patients. Diabetic trauma is one of complications as a result of the interaction of diabetic neuropathy, peripheral vascular disease, infection, trauma, and other factors. Diabetic trauma usually leads to poor healing of the trauma and even to severe foot ulcers, wound gangrene, and even amputation, causing serious psychological, physical, and financial burdens to diabetic patients. Non-coding RNAs (ncRNAs) carried by exosomes have been demonstrated to be relevant to the development and treatment of diabetes and its complications. Exosomes act as vehicle, which contain nucleic acids such as mRNA and microRNA (miRNA), and play a role in the intercellular communication and the exchange of substances between cells. Because exosomes are derived from cells, there are several advantages over synthetic nanoparticle including good biocompatibility and low immunogenicity. Exosomal ncRNAs could serve as markers for the clinical diagnosis of diabetes and could also be employed to accelerate diabetic wound healing via the regulation of the immune response and modulation of cell function. ncRNAs in exosomes can be employed to promote diabetic wound healing by regulating inflammation and accelerating re-vascularization, re-epithelialization, and extracellular matrix remodeling. Herein, exosomes in terms of ncRNA (miRNA, lncRNA, and circRNA) to accelerate diabetic wounds healing were summarized, and we discussed the challenge of the loading strategy of ncRNA into exosomes.