Advanced Science最新文献

Battery-free wireless sensing in extreme environments, such as conductive solutions, is crucial for long-term, maintenance-free monitoring, eliminating the limitations of battery power and enhancing durability in hard-to-reach areas. However, in such environments, the efficiency of wireless power transfer via radio frequecny (RF) energy harvesting is heavily compromised by signal attenuation and environmental interference, which degrade antenna quality factors and detune resonance frequencies. These limitations create substantial challenges in wirelessly powering miniaturized sensor nodes for underwater environmental monitoring. To overcome these challenges, electrically-shielded coils with coaxially aligned dual-layer conductors are introduced that confine the electric field within the coil's inner capacitance. This configuration mitigates electric field interaction with the surrounding medium, making the coils ideal for use as near-field antennas in aquatic applications. Leveraging these electrically-shielded coils, a metamaterial-enhanced reader antenna was developed and a 3-axis sensor antenna for an near-field communication (NFC)-based system. The system demonstrated improved spectral stability, preserving resonance frequency and maintaining a high-quality factor. This advancement enabled the creation of a battery-free wireless sensing platform for real-time environmental monitoring in underwater environments, even in highly conductive saltwater with salinity levels of up to 3.5%.

Intranasal delivery of mRNA vaccines offers promising opportunities to combat airborne viruses like SARS-CoV-2 by provoking mucosal immunity, which not only defends against respiratory infection but also prevents contagious transmission. However, the development of nasal mRNA vaccines has been hampered by the lack of effective means to overcome the mucus barrier. Herein, ionizable lipid-incorporated liquid lipid nanoparticles (iLLNs) capable of delivering mRNA cargo across airway mucosa are designed. Adjusting the ratios of ionizable and cationic lipids allows fine-tuning of the pK_a of iLLNs to the range of nasal mucosal pH (5.5-6.5), thus facilitating mucus penetration via the formation of near-neutral, PEGylated muco-inert surfaces. When nasally administered to mice, the top candidate iLLN-2/mRNA complexes enable about 60-fold greater reporter gene expression in the nasal cavity, compared to the benchmark mRNA-lipid nanoparticles (ALC-LNP) having the same lipid composition as that of BNT162b2 vaccine. Moreover, a prime-boost intranasal immunization of iLLN-2/mRNA complexes elicits a greater magnitude of SARS-CoV-2 spike-specific mucosal IgA and IgG response than ALC-LNP, without triggering any noticeable inflammatory reactions. Taken together, these results provide useful insights for the design of nasally deliverable mRNA formulations for prophylactic applications.

Most antibiotics are ineffective against Gram-negative bacteria owing to the existence of the outer membrane (OM) barrier. The rational design of compounds to expand their antibacterial spectra of antibiotics solely targeting Gram-positive pathogens remains challenging. Here, the design of skeletons from natural products to penetrate the OM are deciphered. Structure-activity relationship analysis shows the optimization of the model of natural xanthones α-mangostin endows the broad-spectrum antibacterial activity. Mechanistic studies demonstrate the lead compound A20 penetrates the OM in a self-promoted pathway through electronic and hydrophobic interactions with lipopolysaccharides and phospholipids in OM. A20 displays rapid bactericidal activity by targeting the cofactor heme in the respiratory complex. The therapeutic efficacy of A20 is demonstrated in two animal models infected with multidrug-resistant Gram-negative bacterial pathogens. The findings elucidate the structural property and self-promoted transportation of a class of antibacterial compounds, to facilitate the design and discovery of antibacterial agents against increasingly prevalent Gram-negative pathogens associated with infections.

Adenosine triphosphate (ATP) is a critical intracellular energy currency that plays a key role in various cellular processes and is closely associated with numerous diseases. Similarly, biothiols such as glutathione (GSH), cysteine (Cys), and homocysteine (Hcy) are integral to many physiological and pathological processes due to their strong redox properties. Simultaneous discrimination and detection of ATP and biothiols offer valuable insights into the pathogenesis of conditions such as epilepsy and liver injury. This study introduces the first fluorescent probe, BCR, designed for multifunctional detection of ATP, GSH, Hcy, and Cys. With outstanding optical properties, excellent biocompatibility, high selectivity, and superior sensitivity, probe BCR enables effective imaging of ATP and biothiol dynamics in vivo. Moreover, probe BCR successfully visualizes changes in ATP, GSH, Hcy, and Cys levels in a PTZ-induced epileptic zebrafish model and an APAP-induced mouse liver injury tissue section model. These findings underscore the significant potential of probe BCR for early disease diagnosis and therapeutic applications.

Immunotherapy has gained approval for use in small cell lung cancer (SCLC), yet only a subset of patients (10-20%) experience meaningful benefits, underscoring the urgent need for more effective therapeutic approaches. This work discovers a distinct HDAC7-high SCLC phenotype characterized by enhanced proliferative potential, which recurs across various subtypes and serves as a predictor of poorer survival outcomes. By analyzing public datasets, this work finds a strong correlation between c-Myc and HDAC7. RNA sequencing and cellular experiments show that XPO1 is a key regulator in the HDAC7/c-Myc axis. HDAC7 promotes β-catenin deacetylation, phosphorylation modulation, nuclear translocation, and formation of the β-catenin/TCF/LEF1 complex, which binds to c-Myc and XPO1 promoters. Activation of the HDAC7/β-catenin pathway upregulates c-Myc and XPO1 expression, while c-Myc also boosts XPO1 expression. Given the difficulty in targeting c-Myc directly, this work tests selinexor and vorinostat in SCLC xenograft models, with selinexor showing superior results. High HDAC7 expression is linked to increased SCLC proliferation, poorer prognosis, and enhanced sensitivity to selinexor in SCLC cell lines and organoid models. Collectively, this work uncovers a novel HDAC7/c-Myc/XPO1 signaling axis that promotes SCLC progression, suggesting that HDAC7 may warrant further investigation as a potential biomarker for assessing selinexor sensitivity in SCLC patients.

Sepsis-induced immunosuppression is related to increased susceptibility to secondary infections and death. Lung is the most vulnerable target organ in sepsis, but the understanding of the pulmonary immunosuppression state is still limited. Here, single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) is performed to map the landscape of immune cells, revealing a neutrophil-driven immunosuppressive program in the lungs of patients with immunosuppressive sepsis. Although immunosuppressive genes are upregulated in different immune cells, only neutrophils dramatically increase in the BALF of patients in immunosuppressive phase of sepsis. Five neutrophil subpopulations in BALF are identified, among which CXCR2⁺ and CD274 (PD-L1 coding gene)⁺IL1RN⁺ neutrophil subpopulations increased significantly during septic immunosuppression. Interestingly, a developmental trajectory from CXCR2⁺ to CD274⁺IL1RN⁺ neutrophil subpopulation is disclosed. Moreover, the therapeutic effect of CXCR2 blockade is observed on the survival of septic mice, along with a decreased number of PD-L1⁺ neutrophils. Taken together, the CXCR2⁺ neutrophil subpopulation is discovered as a contributor to immunosuppression in sepsis and identified it as a potential therapeutic target in sepsis treatment.

The wetting and spreading behaviors of metal droplets on solid substrates are critical aspects of additive manufacturing. However, the inherent characteristics of metal droplets, including high surface tension, elevated viscosity, and extreme temperatures, pose significant challenges for wetting and spreading on nonwetting substrates. Herein, this work proposes a strategy that employs a two-dimensional (2D) orthogonal ultrasonic field to construct a vibration deposition substrate with radial vibration amplitude gradient, thereby enhancing the wettability and adhesive strength of impacting metal droplets ejected by a piezoelectric micro-jet device. First, a 2D ultrasonic vibration device is designed based on the combination of longitudinal vibration modes. Additionally, oblique and circular vibration trajectories are synthesized. The vibration amplitude distributions and trajectories of the deposition substrate are verified utilizing the finite element method. Subsequently, the experimental results demonstrate that the contact angle is decreased by 24.7%, the spreading diameter is increased by 10.3%, and the adhesive strength is enhanced by 5.4 times compared to deposition on a static substrate. The 2D ultrasonic field facilitates the transition of metal droplets from a non-wetting state to a wetting state on the nonwetting substrate, which highlights the versatility and adaptability of ultrasonic strategy for expanding the applications of metal droplets.

The advent of biomacromolecules antagonizing vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular age-related macular degeneration (nAMD). However, frequent intravitreal injections of these biomacromolecules impose an enormous burden on patients and create a massive workload for healthcare providers. This causes patients to abandon therapy, ultimately leading to progressive and irreversible vision loss. In order to address this unmet clinical need, a noninvasive treatment for nAMD is developed. An optimized cell-penetrating peptide derivative, ^bxyPenetratin (bxyWP), is used to non-covalently complex with the anti-VEGF protein aflibercept (AFL) via reversible hydrophobic interaction. The interaction is crucial for AFL delivery, neither impairing the affinity of AFL to pathological VEGF, nor being interfered by endogenous proteins in tear fluids. AFL/bxyWP eye drops exhibit prolonged retention on the eye and excellent absorption into the posterior ocular segment following topical administration, with significant drug distribution to the retina and choroid. In a laser-induced choroidal neovascularization model on cynomolgus monkeys, AFL/bxyWP eye drops efficiently reduce lesion size and leakage comparable to conventional intravitreal injection of AFL. These results suggest that AFL/bxyWP eye drops are feasible self-administered treatment for neovascular retinal diseases and potentially become a substitute for intravitreal injections.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. Although studies have previously investigated metabolic disruptions in the peripheral nervous system (PNS), the exact metabolic mechanisms underlying DPN remain largely unknown. Herein, a specific form of metabolic remodeling involving aberrant ketogenesis within Schwann cells (SCs) in streptozotocin (STZ)-induced type I diabetes mellitus is identified. The PNS adapts poorly to such aberrant ketogenesis, resulting in disrupted energy metabolism, mitochondrial damage, and homeostatic decompensation, ultimately contributing to DPN. Additionally, the maladaptive peripheral ketogenesis is highly dependent on the cannabinoid type-1 receptor (CB₁R)-Hmgcs2 axis. Silencing CB₁R reprogrammed the metabolism of SCs by blocking maladaptive ketogenesis, resulting in rebalanced energy metabolism, reduced histopathological changes, and improved neuropathic symptoms. Moreover, this metabolic reprogramming can be induced pharmacologically using JD5037, a peripheral CB₁R blocker. These findings revealed a new metabolic mechanism underlying DPN, and promoted CB₁R as a promising therapeutic target for DPN.

Oral diseases rank among the most prevalent clinical conditions globally, typically involving detrimental factors such as infection, inflammation, and injury in their occurrence, development, and outcomes. The concentration of reactive oxygen species (ROS) within cells has been demonstrated as a pivotal player in modulating these intricate pathological processes, exerting significant roles in restoring oral functionality and maintaining tissue structural integrity. Due to their enzyme-like catalytic properties, unique composition, and intelligent design, ROS-based nanomaterials have garnered considerable attention in oral nanomedicine. Such nanomaterials have the capacity to influence the spatiotemporal dynamics of ROS within biological systems, guiding the evolution of intra-ROS to facilitate therapeutic interventions. This paper reviews the latest advancements in the design, functional customization, and oral medical applications of ROS-based nanomaterials. Through the analysis of the components and designs of various novel nanozymes and ROS-based nanoplatforms responsive to different stimuli dimensions, it elaborates on their impacts on the dynamic behavior of intra-ROS and their potential regulatory mechanisms within the body. Furthermore, it discusses the prospects and strategies of nanotherapies based on ROS scavenging and generation in oral diseases, offering alternative insights for the design and development of nanomaterials for treating ROS-related conditions.