Nanofiber-mediated sequential photothermal antibacteria and macrophage polarization for healing MRSA-infected diabetic wounds.

BACKGROUND: Diabetic wound healing remains a challenge because of its susceptibility to drug-resistant bacterial infection and its persistent proinflammatory state. Switching from proinflammatory M1 macrophages (Mφs) to proregenerative M2 dominant Mφs in a timely manner accelerates wound healing by coordinating inflammatory, proliferative, and angiogenic processes. METHODS: We propose a sequential photothermal antibacterial and subsequent M2 Mφ polarization strategy based on nanofibers (NFs) consisting of polydopamine (PDA) coating on curcumin (Cur) nanocrystals to treat Methicillin-resistant Staphylococcus aureus (MRSA)-infected diabetic wounds. RESULTS: The PDA/Cur NFs showed excellent photothermal conversion and antibacterial effects due to the PDA shell under laser irradiation, consequently resulting in the release of the inner Cur with the ability to promote cell proliferation and reinforce the M2 Mφ phenotype in vitro. In vivo studies on MRSA-infected diabetic wounds showed that PDA/Cur NFs not only inhibited MRSA infection but also accelerated the wound regeneration process. Furthermore, the NFs displayed the ability to promote the M2 Mφ phenotype with enhanced collagen deposition, angiogenesis, and cell proliferation. CONCLUSION: Overall, the NFs displayed great potential as promising therapeutics for healing infected diabetic wounds through a sequential photothermal antibacterial and M2 Mφ polarization strategy.

Neuromedin B regulates steroidogenesis, cell viability and apoptosis in rabbit Leydig cells.

Mammalian bombesin-related peptide, neuromedin B (NMB) action is mediated by its receptor (NMBR), and NMB/NMBR system plays a major role in regulating hormone secretions, reproduction and cell growth. Here we report the functions of NMB in regulating steroidogenesis (testosterone synthesis), cell viability and apoptosis. The primary rabbit Leydig cells were employed as the paradigm for this research. We initially confirmed that NMBR is distributed in Leydig cells of rabbit testis, and a certain dose of NMB could increase the secretion of testosterone in primary cultured rabbit Leydig cells. Subsequently, the accumulated NMBR, StAR, CYP11A1, 3ß-HSD and PKC protein could be induced by a certain dose of NMB in Leydig cells. Moreover, we found that NMB could decrease the cell viability, and decreased the expression of PCNA protein in Leydig cells; meanwhile, except for 100 nM, other doses of NMB could suppress the cell apoptosis, and regulate Caspase-3 protein expression in Leydig cells, respectively. These results identify that NMB may be a key factor in regulating testosterone synthesis through taking part in NMBR/PKC/steroidogenesis signaling pathway, as well as the cell viability and proliferation in rabbit Leydig cells.

Characterization of an Escherichia coli phage Tequatrovirus YZ2 and its application in bacterial wound infection.

The increasing prevalence of drug-resistant Escherichia coli (E. coli) resulting from the excessive utilization of antibiotics necessitates the immediate exploration of alternative approaches to counteract pathogenic E. coli. Phages, with their unique antibacterial mechanisms, are considered promising candidates for treating bacterial infections. Herein, we isolated a lytic Escherichia phage Tequatrovirus YZ2 (phage YZ2), which belongs to the genus Tequatrovirus. The genome of phage YZ2 consists of 168,356 base pairs with a G + C content of 35.34% and 269 putative open reading frames (ORFs). Of these, 146 ORFs have been annotated as functional proteins associated with nucleotide metabolism, structure, transcription, DNA replication, translation, and lysis. In the mouse model of a skin wound infected by E. coli, phage YZ2 therapy significantly promoted the wound healing. Furthermore, histopathological analysis revealed reductions in IL-1ß and TNF-α and increased VEGF levels, indicating the potential of phages as effective antimicrobial agents against E. coli infection.

Self-Assembled Virus-Like Particle Vaccines via Fluorophilic Interactions Enable Infection Mimicry and Immune Protection.

Influenza epidemics persistently threaten global health. Vaccines based on virus-like particles (VLPs), which resemble the native conformation of viruses, have emerged as vaccine candidates. However, the production of VLPs via genetic engineering remains constrained by challenges such as low yields, high costs, and being time consuming. In this study, a novel VLP platform is developed that could mimic infection and confer influenza protection through fluorination-driven self-assembly. The VLPs closely mimick the key steps in viral infection including dendritic cell (DC) attachment and pH-responsive endo-lysosomal escape, which enhances DC maturation and antigen cross-presentation. It is also observed that the VLPs migrate from the injection site to the draining lymph nodes efficiently. Immunization with VLPs triggers both Th1 and Th2 cellular responses, thereby inducing an improved CD8+ T cell response along with strong antigen-specific antibody responses. In several infected mouse models, VLP vaccines ameliorate weight loss, lung virus titers, pulmonary pathologies, and confer full protection against H1N1, H6N2, H9N2, and mixed influenza viruses. Therefore, the results support the potential of VLPs as an effective influenza vaccine with improved immune potency against infection. A methodology to generate VLPs based on fluorophilic interactions, which can be a general approach for development of pathogenic VLPs, is reported.

Erythrocyte-enabled immunomodulation for vaccine delivery.

Erythrocytes capture pathogens in circulation and present them to antigen-presenting cells (APCs) in the spleen. Senescent or apoptotic erythrocytes are physiologically eliminated by splenic APCs in a non-inflammatory manner as to not induce an immune reaction, while damaged erythrocytes tend to induce immune activation. The distinct characteristics of erythrocytes in their lifespan or different states inspire the design of targeting splenic APCs for vaccine delivery. Specifically, normal or damaged erythrocyte-driven immune targeting can induce antigen-specific immune activation, whereas senescent or apoptotic erythrocytes can be tailored to achieve antigen-specific immune tolerance. Recent studies have revealed the potential of erythrocyte-based vaccine delivery; however, there is still no in-depth review to describe the latest progress. This review summarizes the characteristics, different immune functions, and diverse vaccine delivery behaviors and biomedical applications of erythrocytes in different states. This review aims to contribute to the rational design and development of erythrocyte-based vaccine delivery systems for treating various infections, tumors, inflammatory diseases, and autoimmune diseases.

Delivery of nanoparticle antigens to antigen-presenting cells: from extracellular specific targeting to intracellular responsive presentation.

An appropriate delivery system can improve the immune effects of antigens against various infections or tumors. Antigen-presenting cells (APCs) are specialized to capture and process antigens in vivo, which link the innate and adaptive immune responses. Functionalization of vaccine delivery systems with targeting moieties to APCs is a promising strategy for provoking potent immune responses. Additionally, the internalization and intracellular distribution of antigens are closely related to the initiation of downstream immune responses. With a deeper understanding of the intracellular microenvironment and the mechanisms of antigen presentation, vehicles designed to respond to endogenous and external stimuli can modulate antigen processing and presentation pathways, which are critical to the types of immune response. Here, an overview of extracellular targeting delivery of antigens to APCs and intracellular stimulus-responsiveness strategies is provided, which might be helpful for the rational design of vaccine delivery systems.