Allergen-specific immunotherapy (AIT) is the only treatment that addresses the root cause of immunoglobulin E (IgE)-mediated allergies, but conventional methods face challenges with treatment duration, patient compliance, and adverse effects. In this study, we propose intratonsillar immunotherapy (ITIT) as a new effective and safer route for AIT. Prior to clinical trials, we analyzed tonsil samples from human subjects to assess immune responses, measuring interleukin-4 (IL-4), IL-21, total IgE (tIgE), and allergen-specific IgE concentrations using ELISA and BioIC. Our results indicated that tonsils contained higher levels of allergen-specific IgE compared to peripheral blood. In the clinical phase, 120 allergic rhinitis (AR) patients were treated with either 3 intratonsillar allergen injections over 2 months or conventional subcutaneous immunotherapy (SCIT) over 1 year. ITIT demonstrated superior and faster symptom relief, especially in younger patients, while requiring markedly fewer doses and injections than SCIT. Immunological analysis revealed reduced eosinophil counts, increased regulatory T (T_reg) and follicular regulatory T (T_FR) cell levels, and a favorable shift in cytokine profiles. Adverse events were minimal, and the treatment showed high patient compliance. These findings suggest that ITIT could provide an effective, safer, and more convenient alternative to AIT.

Electromagnetic (EM) metamaterials represent a cutting-edge field that achieves anomalously macroscopic properties through artificial design and arrangement of microstructure arrays to freely manipulate EM fields and waves in desired ways. The unit cell of a microstructure array is also called a meta-atom, which can construct effective medium parameters that do not exist in traditional materials or are difficult to realize with traditional technologies. By deep integration with digital information, the meta-atom is evolved to a digital meta-atom, leading to the emergence of information metamaterials. Information metamaterials break the inherent barriers between the EM and digital domains, providing a physical platform for controlling EM waves and modulating digital information simultaneously. The concepts of meta-atoms and metamaterials are also introduced to high-frequency integrated circuit designs to address issues that cannot be solved by traditional methods, since lumped-parameter models become unsustainable at microscopic scales. By incorporating several meta-atoms to form a metachip, precise manipulation of the EM field distribution can be achieved at microscopic scales. In this perspective, we summarize the physical connotations and main classifications of meta-atoms and briefly discuss their future development trends. Through this article, we hope to draw more research attention to explore the potential values of meta-atoms, thereby opening up a broader stage for the in-depth development of metamaterials.

Sepsis-associated encephalopathy (SAE) is a severe and frequent septic complication, characterized by neuronal damage as key pathological features. The astrocyte–microglia crosstalk in the central nervous system (CNS) plays important roles in various neurological diseases. However, how astrocytes interact with microglia to regulate neuronal injury in SAE is poorly defined. In this study, we aim to investigate the molecular basis of the astrocyte–microglia crosstalk underlying SAE pathogenesis and also to explore the new therapeutic strategies targeting this crosstalk in this devastating disease. We established a human astrocyte/microglia coculture system on a microfluidic device, which allows real-time and high-resolution recording of glial responses to inflammatory stimuli. Based on this microfluidic system, we can test the responses of astrocytes and microglia to lipopolysaccharide (LPS) treatment, and identify the molecular cues that mediate the astrocyte–microglia crosstalk underlying the pathological condition. In addition, the SAE mouse model was utilized to determine the state of glial cells and evaluate the therapeutic effect of drugs targeting the astrocyte–microglia crosstalk in vivo. Here, we found that activated astrocytes and microglia exhibited close spatial interaction in the SAE mouse model. Upon LPS exposure for astrocytes, we detected that more microglia migrated to the central astrocyte culture compartment on the microfluidic device, accompanied by M1 polarization and increased cell motility in microglia. Cytokine array analysis revealed that less interleukin 11 (IL11) was secreted by astrocytes following LPS treatment, which further promoted reprogramming of microglia to pro-inflammatory M1 phenotype via the nuclear factor-κB (NF-κB) signaling pathway. Intriguingly, we found that IL11 addition markedly rescued LPS-induced neuronal injuries on the microfluidic system and brain injury in the SAE mouse model. This study defines an unknown crosstalk of astrocyte–microglia mediated by IL11, which contributed to the neuropathogenesis of SAE, and suggested a potential therapeutic value of IL11 in the devastating disease.

Excessive fibrosis is the primary factor for the failure of glaucoma drainage device (GDD) implantation. Thus, strategies to suppress scar formation in GDD implantation are crucial. Although it is known that in implanted medical devices, microscale modification of the implant surface can modulate cell behavior and reduce the incidence of fibrosis, in the field of ophthalmic implants, especially the modification and effects of hydrogel micropatterns have rarely been reported. Here, we designed the patterned gelatin/acrylamide double network hydrogel and developed an innovative GDD with micropattern to suppress inflammatory and fibroblast activation after GDD implantation. Pattern topography suppressed F-actin expression and mitigated actin-dependent nuclear migration of myocardin-related transcription factor A (MRTF-A) during the proliferative phase after GDD implantation. Ultimately, the expression of α-smooth muscle actin (α-SMA), a key fibrosis-related gene product, was suppressed. Moreover, the modified GDD effectively controlled intraocular pressure (IOP), mitigated fibrous formation, and remodeled extracellular matrix (ECM) collagen distribution in vivo. Therefore, the novel GDD with surface patterning interventions provides a promising strategy to inhibit scar formation after GDD implantation and raise the efficacy of GDD implantation.

Na_v1.7 is considered a promising target for developing next-generation analgesic drugs, given its critical role in human pain pathologies. Although most reported inhibitors with strong in vitro activity and high selectivity share the aryl sulfonamide scaffold, they failed to demonstrate marked clinical efficacy. Therefore, exploring new Na_v1.7-selective antagonists is quite urgent to the development of next-generation analgesic drugs. Here, we report a highly effective 1H-indole-3-propionamide inhibitor, WN2, identified through an integrated drug discovery strategy. Notably, the structure of WN2 is quite different from previously reported aryl sulfonamide inhibitors. Molecular dynamics simulations and experimental findings reveal that the R configuration of WN2 (WN2-R) is the preferred form (IC₅₀ = 24.7 ± 9.4 nM) within the VSDIV pocket of Na_v1.7. WN2-R exhibits impressive analgesic effects in acute and chronic inflammatory pain, as well as neuropathic pain models in mice. Additionally, it displays favorable subtype selectivity and positive drug safety in acute toxicity studies. Pharmacokinetic studies indicate that WN2-R has high bioavailability (F = 20.29%), highlighting its considerable potential for drug development. Our study establishes WN2-R as a novel Na_v1.7-selective inhibitor with a unique structural scaffold, offering a promising candidate for the next generation of analgesic drugs.

Hyperglycemia and bacterial colonization in diabetic wounds aberrantly activate Nod-like receptor protein 3 (NLRP3) in macrophages, resulting in extensive inflammatory infiltration and impaired wound healing. Targeted suppression of the NLRP3 inflammasome shows promise in reducing macrophage inflammatory disruptions. However, challenges such as drug off-target effects and degradation via lysosomal capture remain during treatment. In this study, engineered apoptotic bodies (BHB-dABs) derived from adipose stem cells loaded with β-hydroxybutyric acid (BHB) were synthesized via biosynthesis. These vesicles target M1-type macrophages, which highly express the folic acid receptor in the inflammatory microenvironment, and facilitate lysosomal escape through 1,2-distearoyl-sn-propyltriyl-3-phosphatidylethanolamine–polyethylene glycol functionalization, which may enhance the efficacy of NLRP3 inhibition for managing diabetic wounds. In vitro studies demonstrated the biocompatibility of BHB-dABs, their selective targeting of M1-type macrophages, and their ability to release BHB within the inflammatory microenvironment via folic acid and folic acid receptor signaling. These nanovesicles exhibited lysosomal escape, anti-inflammatory, mitochondrial protection, and endothelial cell vascularization properties. In vivo experiments demonstrated that BHB-dABs enhance the recovery of diabetic wound inflammation and angiogenesis, accelerating wound healing. These functionalized apoptotic bodies efficiently deliver NLRP3 inflammasome inhibitors using a dual strategy of targeting macrophages and promoting lysosomal escape. This approach represents a novel therapeutic strategy for effectively treating chronic diabetic wounds.

Background: Chimeric antigen receptor (CAR)-based immune cell therapies attack neighboring cancer cells after receptor recognition but are unable to directly affect distant tumor cells. This limitation may contribute to their inefficiency in treating solid tumors, given the restricted intratumoral infiltration and immunosuppressive tumor microenvironment. Therefore, cell–cell fusion as a cell-killing mechanism might develop a novel cytotherapy aimed at improving the efficacy against solid tumors. Methods: We constructed a fusogenic protein, fusion-associated small transmembrane (FAST) p14 of reptilian reovirus, into cancer cells and mesenchymal stem cells (MSCs), which cocultured with various colon cancer cells and melenoma cells to validate its ability to induce cell fusion and syncytia formation. RNA sequencing, quantitative reverse transcription polymerase chain reaction, and Western blot were performed to elucidate the mechanism of syncytia death. Cell viability assay was employed to assess the killing effects of MSCs carrying the p14 protein (MSCs-p14), which was also identified in the subcutaneous tumor models. Subsequently, the Tet-On system was introduced to enhance the controllability and safety of therapy. Results: Cancer cells incorporated with fusogenic protein p14 FAST from reovirus fused together to form syncytia and subsequently died through apoptosis and pyroptosis. MSCs-p14 cocultured with different cancer cells and effienctly induced cancer cell fusion and caused widespread cancer cell death in vitro. In mouse tumor models, mMSCs-p14 treatment markedly suppressed tumor growth and also enhanced the activity of natural killer cells and macrophages. Controllability and safety of MSCs-p14 therapy were further improved by introducing the tetracycline-controlled transcriptional system. Conclusion: MSC-based cytotherapy carrying viral fusogenic protein in this study kills cancer cells by inducing cell–cell fusion. It has demonstrated definite efficacy in treating solid tumors and is worth considering for clinical development.

Metals have traditionally served as the primary functional phase in the development of metamaterials exhibiting epsilon-near-zero (ENZ) and epsilon-negative (EN) responses, albeit with persisting ambiguities regarding their response mechanisms. This paper presents the tunable ENZ (ε′ ~ 0) and EN (ε′ < 0) parameters at the 20-MHz to 1-GHz region based on Cu/CaCu₃Ti₄O₁₂ (Cu/CCTO) metacomposites. By means of first-principles calculations and multi-physics simulations, the underlying mechanisms governing ENZ and EN responses are unveiled. The intricate pathways through which metacomposites achieve 2 dielectric response mechanisms are delineated: At low Cu content, a weak EN response (|ε′| < 200) was excited by electric dipole resonance, accompanied by ENZ effect; conversely, at high Cu content, due to the increase in effective electron concentration, plasmonic oscillation behavior occurs in the constructed 3-dimensional Cu network, resulting in strong EN response (|ε′| ~ 1,000) in the radio frequency band. These phenomena are explicated through 2 distinct Cu/CCTO models: Cu in an isolated state and a connected network state. This study not only comprehensively elucidates the 2 EN response mechanisms achieved by typical metacomposites with metals as functional phases but also delves into their associated electromagnetic shielding and thermal properties, providing a theoretical basis for their practical applications.

The engineering design and construction of active interfaces represents a promising approach amidst numerous initiatives aimed at augmenting catalytic activity. Herein, we present a novel approach to incorporate interconnected pores within bulk single crystals for the synthesis of macroscopic porous single-crystalline rutile titanium oxide (R-TiO₂). The porous single crystal (PSC) R-TiO₂ couples a nanocrystalline framework as the solid phase with pores as the fluid phase within its structure, providing unique advantages in localized structure construction and in the field of catalysis. We successfully construct well-defined Ni cluster/TiO₂ active interfaces by directly confining Ni clusters on the continuous lattice surface of PSC R-TiO₂. We confirm that the lattice oxygen connected to the Ni clusters exhibits exceptional activation capability at temperatures close to room temperature compared to the pure phase PSC R-TiO₂ monoliths. The PSC Ni/TiO₂ catalyst demonstrates complete CO oxidation and stable catalytic performance during continuous operation in air at ~80 °C for 200 h.

Transfer RNA-derived small RNAs, a recently identified class of small noncoding RNAs, play a crucial role in regulating gene expression and are implicated in cerebrovascular diseases. However, the specific biological roles and mechanisms of transfer RNA-derived small RNAs in intracranial aneurysms (IAs) remain unclear. In this study, we identified that the transfer RNA-Asp-GTC derived fragment (tRF-AspGTC) is highly expressed in the IA tissues of both humans and mice. tRF-AspGTC promotes IA formation by facilitating the phenotypic switching of vascular smooth muscle cells, increasing of matrix metalloproteinase 9 expression, and inducing of oxidative stress and inflammatory responses. Mechanistically, tRF-AspGTC binds to galectin-3, inhibiting tripartite motif 29-mediated ubiquitination and stabilizing galectin-3. This stabilization activates the toll-like receptor 4/MyD88/nuclear factor kappa B pathway, further driving phenotypic switching and inflammation. Clinically, circulating exosomal tRF-AspGTC demonstrates strong diagnostic efficacy for IAs and is identified as an independent risk factor for IA occurrence. These findings highlight the potential of tRF-AspGTC as a promising diagnostic biomarker and therapeutic target for IAs.