Plasticity in single-crystalline Mg3Bi2 thermoelectric material.

Most of the state-of-the-art thermoelectric materials are inorganic semiconductors. Owing to the directional covalent bonding, they usually show limited plasticity at room temperature1,2, for example, with a tensile strain of less than five per cent. Here we discover that single-crystalline Mg3Bi2 shows a room-temperature tensile strain of up to 100 per cent when the tension is applied along the (0001) plane (that is, the ab plane). Such a value is at least one order of magnitude higher than that of traditional thermoelectric materials and outperforms many metals that crystallize in a similar structure. Experimentally, slip bands and dislocations are identified in the deformed Mg3Bi2, indicating the gliding of dislocations as the microscopic mechanism of plastic deformation. Analysis of chemical bonding reveals multiple planes with low slipping barrier energy, suggesting the existence of several slip systems in Mg3Bi2. In addition, continuous dynamic bonding during the slipping process prevents the cleavage of the atomic plane, thus sustaining a large plastic deformation. Importantly, the tellurium-doped single-crystalline Mg3Bi2 shows a power factor of about 55 microwatts per centimetre per kelvin squared and a figure of merit of about 0.65 at room temperature along the ab plane, which outperforms the existing ductile thermoelectric materials3,4.

SENP3 senses oxidative stress to facilitate STING-dependent dendritic cell antitumor function.

STING-dependent cytosolic DNA sensing in dendritic cells (DCs) initiates antitumor immune responses, but how STING signaling is metabolically regulated in the tumor microenvironment remains unknown. Here, we show that oxidative stress is required for STING-induced DC antitumor function through a process that directs SUMO-specific protease 3 (SENP3) activity. DC-specific deletion of Senp3 drives tumor progression by blunting STING-dependent type-I interferon (IFN) signaling in DCs and dampening antitumor immune responses. DC-derived reactive oxygen species (ROS) trigger SENP3 accumulation and the SENP3-IFI204 interaction, thereby catalyzing IFI204 deSUMOylation and boosting STING signaling activation in mice. Consistently, SENP3 senses ROS to facilitate STING-dependent DC activity in tissue samples from colorectal cancer patients. Our results reveal that oxidative stress as a metabolic regulator promotes STING-mediated DC antitumor immune responses and highlights SENP3 as an overflow valve for STING signaling induction in the metabolically abnormal tumor microenvironment.

The role of fatty acid metabolism in acute lung injury: a special focus on immunometabolism.

Reputable evidence from multiple studies suggests that excessive and uncontrolled inflammation plays an indispensable role in mediating, amplifying, and protracting acute lung injury (ALI). Traditionally, immunity and energy metabolism are regarded as separate functions regulated by distinct mechanisms, but recently, more and more evidence show that immunity and energy metabolism exhibit a strong interaction which has given rise to an emerging field of immunometabolism. Mammalian lungs are organs with active fatty acid metabolism, however, during ALI, inflammation and oxidative stress lead to a series metabolic reprogramming such as impaired fatty acid oxidation, increased expression of proteins involved in fatty acid uptake and transport, enhanced synthesis of fatty acids, and accumulation of lipid droplets. In addition, obesity represents a significant risk factor for ALI/ARDS. Thus, we have further elucidated the mechanisms of obesity exacerbating ALI from the perspective of fatty acid metabolism. To sum up, this paper presents a systematical review of the relationship between extensive fatty acid metabolic pathways and acute lung injury and summarizes recent advances in understanding the involvement of fatty acid metabolism-related pathways in ALI. We hold an optimistic believe that targeting fatty acid metabolism pathway is a promising lung protection strategy, but the specific regulatory mechanisms are way too complex, necessitating further extensive and in-depth investigations in future studies.

Ethylene Methoxycarbonylation over Heterogeneous Pt1/MoS2 Single-Atom Catalyst: Metal-Support Concerted Catalysis.

Ethylene methoxycarbonylation (EMC) to methyl propanoate (MP) is an industrially important reaction and commercially uses a homogeneous Pd-phosphine organometallic complex as the catalyst and corrosive strong acid as the promoter. In this work, we develop a Pt1/MoS2 heterogeneous single-atom catalyst (SAC) which exhibits high activity, selectivity, and good recyclability for EMC reaction without need of any liquid acid. The production rate of MP achieves 0.35 gMP gcat-1 h-1 with MP selectivity of 91.1% at 1 MPa CO, 1 MPa C2H4, and 160 °C, which can be doubled at 2 MPa CO and corresponds to 320.1 molMP molPt-1 h-1, at least 1 order of magnitude higher than the earlier reported heterogeneous catalyst and even comparable to some of homogeneous catalyst. Advanced characterizations and DFT calculations reveal that all the Pt single atoms are located at the Mo vacancies along the Mo edge of the MoS2 nanosheets, forming pocket-like Mo-S-Pt1-S-Mo ensembles with uniform and well-defined structure. Methanol is first adsorbed and dissociated on Mo sites, and the produced H spillovers to the adjacent Pt site forming Pt-H species which then activate ethylene, forming Pt-ethyl species. Meanwhile, CO adsorbed on the other Mo site reacts with the Pt-ethyl species, yielding propionyl species, and this carbonylation is the rate-determining step. The final methoxylation step proceeds via the nucleophilic attack of propionyl species by -OCH3 affording the final product MP. Such a metal-support concerted catalysis enabled by the Mo-S-Pt1-S-Mo multisite ensemble opens a new avenue for SACs to promote the multimolecular reactions that prevail in homogeneous catalysis.

Bactericidal and sterilizing activity of sudapyridine-clofazimine-TB47 combined with linezolid or pyrazinamide in a murine model of tuberculosis.

As an obligate aerobe, Mycobacterium tuberculosis relies on its branched electron transport chain (ETC) for energy production through oxidative phosphorylation. Regimens targeting ETC exhibit promising potential to enhance bactericidal activity against M. tuberculosis and hold the prospect of shortening treatment duration. Our previous research demonstrated that the bacteriostatic drug candidate TB47 (T) inhibited the growth of M. tuberculosis by targeting the cytochrome bc1 complex and exhibited synergistic activity with clofazimine (C). Here, we found synergistic activities between C and sudapyridine (S), a structural analog of bedaquiline (B). S has shown similar anti-tuberculosis efficacy and may share a mechanism of action with B, which inhibits ATP synthesis and the energy metabolism of bacteria. We evaluated the efficacy of SCT in combination with linezolid (L) or pyrazinamide (Z) using a well-established murine model of tuberculosis. Compared to the BPa(pretomanid)L regimen, SCT and SCTL demonstrated similar bactericidal and sterilizing activities. There was no significant difference in activity between SCT and SCTL. In contrast, SCZ and SCTZ showed much higher activities, with none of the 15 mice experiencing relapse after 2 months of treatment with either SCZ or SCTZ. However, T did not contribute to the activity of the SCZ. Our findings emphasize the efficacy and the potential clinical significance of combination therapy with ETC inhibitors. Additionally, cross-resistance exists not only between S and B but also between S/B and C. This is supported by our findings, as spontaneous S-resistant mutants exhibited mutations in Rv0678, which are associated with cross-resistance to B and C.

Hyaluronic acid-modified mesoporous silica nanoprobes for target identification of atherosclerosis.

Rupture of vulnerable plaque and secondary thrombosis caused by atherosclerosis are one of the main causes of acute cardiovascular and cerebrovascular events, and it is urgent to develop an in-situ, noninvasive, sensitive and targeted detection method at molecular level. We chose CD44, a specific receptor highly expressed on the surface of macrophages, as the target of the molecular probe, and modified the CD44 ligand HA onto the surface of Gd2O3@MSN, constructing the MRI imaging nanoprobe HA-Gd2O3@MSN for targeted recognition of atherosclerosis. The fundamental properties of HA-Gd2O3@MSN were initially investigated. The CCK-8, hemolysis, hematoxylin-eosin staining tests and blood biochemical assays confirmed that HA-Gd2O3@MSN possessed excellent biocompatibility. Laser confocal microscopy, cellular magnetic resonance imaging, flow cytometry and immunohistochemistry were used to verify that the nanoprobes had good targeting properties. The in vivo targeting performance of the nanoprobes was further validated by employing a rabbit atherosclerosis animal model. In summary, the synthesized HA-Gd2O3@MSN nanoprobes have excellent biocompatibility properties as well as good targeting properties. It could provide a new technical tool for early identification of atherosclerosis.

BI-RADS Category Assignments by GPT-3.5, GPT-4, and Google Bard: A Multilanguage Study.

Background The performance of publicly available large language models (LLMs) remains unclear for complex clinical tasks. Purpose To evaluate the agreement between human readers and LLMs for Breast Imaging Reporting and Data System (BI-RADS) categories assigned based on breast imaging reports written in three languages and to assess the impact of discordant category assignments on clinical management. Materials and Methods This retrospective study included reports for women who underwent MRI, mammography, and/or US for breast cancer screening or diagnostic purposes at three referral centers. Reports with findings categorized as BI-RADS 1-5 and written in Italian, English, or Dutch were collected between January 2000 and October 2023. Board-certified breast radiologists and the LLMs GPT-3.5 and GPT-4 (OpenAI) and Bard, now called Gemini (Google), assigned BI-RADS categories using only the findings described by the original radiologists. Agreement between human readers and LLMs for BI-RADS categories was assessed using the Gwet agreement coefficient (AC1 value). Frequencies were calculated for changes in BI-RADS category assignments that would affect clinical management (ie, BI-RADS 0 vs BI-RADS 1 or 2 vs BI-RADS 3 vs BI-RADS 4 or 5) and compared using the McNemar test. Results Across 2400 reports, agreement between the original and reviewing radiologists was almost perfect (AC1 = 0.91), while agreement between the original radiologists and GPT-4, GPT-3.5, and Bard was moderate (AC1 = 0.52, 0.48, and 0.42, respectively). Across human readers and LLMs, differences were observed in the frequency of BI-RADS category upgrades or downgrades that would result in changed clinical management (118 of 2400 [4.9%] for human readers, 611 of 2400 [25.5%] for Bard, 573 of 2400 [23.9%] for GPT-3.5, and 435 of 2400 [18.1%] for GPT-4; P < .001) and that would negatively impact clinical management (37 of 2400 [1.5%] for human readers, 435 of 2400 [18.1%] for Bard, 344 of 2400 [14.3%] for GPT-3.5, and 255 of 2400 [10.6%] for GPT-4; P < .001). Conclusion LLMs achieved moderate agreement with human reader-assigned BI-RADS categories across reports written in three languages but also yielded a high percentage of discordant BI-RADS categories that would negatively impact clinical management. © RSNA, 2024 Supplemental material is available for this article.

Synergistic Effects of Amine Functional Groups and Enriched-Atomic-Iron Sites in Carbon Dots for Industrial-Current-Density CO2 Electroreduction.

Metal phthalocyanine molecules with Me-N4 centers have shown promise in electrocatalytic CO2 reduction (eCO2R) for CO generation. However, iron phthalocyanine (FePc) is an exception, exhibiting negligible eCO2R activity due to a higher CO2 to *COOH conversion barrier and stronger *CO binding energy. Here, amine functional groups onto atomic-Fe-rich carbon dots (Af-Fe-CDs) are introduced via a one-step solvothermal molecule fusion approach. Af-Fe-CDs feature well-defined Fe-N4 active sites and an impressive Fe loading (up to 8.5 wt%). The synergistic effect between Fe-N4 active centers and electron-donating amine functional groups in Af-Fe-CDs yielded outstanding CO2-to-CO conversion performance. At industrial-relevant current densities exceeding 400 mA cm-2 in a flow cell, Af-Fe-CDs achieved >92% selectivity, surpassing state-of-the-art CO2-to-CO electrocatalysts. The in situ electrochemical FTIR characterization combined with theoretical calculations elucidated that Fe-N4 integration with amine functional groups in Af-Fe-CDs significantly reduced energy barriers for *COOH intermediate formation and *CO desorption, enhancing eCO2R efficiency. The proposed synergistic effect offers a promising avenue for high-efficiency catalysts with elevated atomic-metal loadings.

Phospholipid-Anchored Ligand Conjugation on Extracellular Vesicles for Enhanced Cancer Targeting.

Extracellular vesicles (EVs) are recognized as potential candidates for next-generation drug delivery systems. However, the inherent cancer-targeting efficiency is unsatisfactory, necessitating surface modification to attach cell-binding ligands. By utilizing phospholipase D from Streptomyces in combination with maleimide-containing primary alcohol, the authors successfully anchored ligands onto milk-derived EVs (mEVs), overcoming the issues of ligand leakage or functional alteration seen in traditional methods. Quantitative nano-flow cytometry demonstrated that over 90% of mEVs are effectively modified with hundreds to thousands of ligands. The resulting mEV formulations exhibited remarkable long-term stability in conjugation proportion, ligand number, size distribution, and particle concentration, even after months of storage. It is further shown that conjugating transferrin onto mEVs significantly enhanced cellular uptake and induced pronounced cytotoxic effects when loaded with paclitaxel. Overall, this study presents a highly efficient, stable, cost-effective, and scalable ligand conjugation approach, offering a promising strategy for targeted drug delivery of EVs.

Charge Carriers Localization Effect Revealed through Terahertz Spectroscopy of MXene: Ti3C2Tx.

The transport properties of charge carriers in MXene, a promising material, have been studied using terahertz time-domain spectroscopy (THz-TDS) to examine its potential applications in optical and electronic devices. However, previous studies have been limited by narrow frequency ranges, which have hindered the understanding of the intrinsic mechanisms of carrier transport in MXenes. To address this issue, ultrabroadband THz-TDS with frequencies of up to 15 THz to investigate the complex photoconductances of MXene (Ti3C2Tx) films with different thicknesses are employed. The findings indicate that the electronic localization is substrate-dependent, and this effect decreases with an increase in the number of layers. This is attributed to the screening effect of the high carrier density in Ti3C2Tx. Additionally, the layer-independent photocarrier relaxations revealed by optical pump THz probe spectroscopy (OPTP) provide evidence of the carrier heating-induced screening effect. These results are significant for practical applications in both scientific research and various industries.

Integrative single-cell analysis reveals distinct adaptive immune signatures in the cutaneous lesions of pemphigus.

Pemphigus, an autoimmune bullous disease affecting the skin and mucosal membranes, is primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the underlying immune mechanisms of this disease remain largely elusive. Here, we compile an unbiased atlas of immune cells in pemphigus cutaneous lesions at single-cell resolution. We reveal clonally expanded antibody-secreting cells (ASCs) that exhibit variable hypermutation and accumulation of IgG4 class-switching in their immunoglobulin genes. Importantly, pathogenic Dsg-specific ASCs are localized within pemphigus lesions and can evolve from both Dsg-autoreactive and non-binding precursors. We observe an altered distribution of CD4+ T cell subsets within pemphigus lesions, including an imbalance of Th17/Th2 cells. Significantly, we identify a distinct subpopulation of Th17 cells expressing CXCL13 and IL-21 within pemphigus lesions, implying its pivotal role in B cell recruitment and local production of autoantibodies. Furthermore, we characterize multiple clonally expanded CD8+ subpopulations, including effector GMZB+ and GMZK+ subsets with augmented cytotoxic activities, within pemphigus lesions. Chemokine-receptor mapping uncovers cell-type-specific signaling programs involved in the recruitment of T/B cells within pemphigus lesions. Our findings significantly contribute to advancing the understanding of the heterogeneous immune microenvironment and the pathogenesis of pemphigus cutaneous lesions, thereby providing valuable insights for potential therapeutic interventions in this disease.

High-precision spatiotemporal three-dimensional ultrashort pulse synchronization with optical Kerr effect.

In studying the interaction of multiple ultrashort pulses with matter, high requirements are put forward for spatiotemporal synchronization accuracy. Limited by the response time and bandwidth of existing devices, the synchronization of multiple ultrashort pulses still faces significant difficulties. By observing the transient phenomena of the optical Kerr effect, high-precision, three-dimensional (x, y, t) synchronization of ultrashort pulses at different angles was achieved. In the optical Kerr effect, the polarization state of the signal pulse changes only when it coincides with the pump pulse, at which point the signal pulse passes through the analyzer. The changes in the intensity and phase of the signal pulse is positively correlated with the degree of spatiotemporal coincidence. In this study, 10-ps pulses were used in the experiments. By observing the intensity and phase distribution of the signal pulses, a time synchronization accuracy between two pulses of less than 1 ps and spatial synchronization accuracy of ±125 µm and ±3 µm in the x and y directions, respectively, were achieved. Moreover, the synchronization of two pulses at an angle of 90 ° was measured, further proving that the method can achieve the spatiotemporal synchronization of pulses with large angles. Therefore, this method has important application prospects in the study of multi-beam interactions with matter and other ultrafast physical phenomena.

Expanding the Chemical Diversity of Grisechelins via Heterologous Expression.

Thiazole scaffold-based small molecules exhibit a range of biological activities and play important roles in drug discovery. Based on bioinformatics analysis, a putative biosynthetic gene cluster (BGC) for thiazole-containing compounds was identified from Streptomyces sp. SCSIO 40020. Heterologous expression of this BGC led to the production of eight new thiazole-containing compounds, grisechelins E, F, and I-N (1, 2, 5-10), and two quinoline derivatives, grisechelins G and H (3 and 4). The structures of 1-10, including their absolute configurations, were elucidated by HRESIMS, NMR spectroscopic data, ECD calculations, and single-crystal X-ray diffraction analysis. Grisechelin F (2) is a unique derivative, distinguished by the presence of a salicylic acid moiety. The biosynthetic pathway for 2 was proposed based on bioinformatics analysis and in vivo gene knockout experiments. Grisechelin E (1) displayed moderate antimycobacterial activity against Mycobacterium tuberculosis H37Ra (MIC of 8 µg mL-1).

Effect of pericapsular nerve group block and suprainguinal fascia iliaca block on postoperative analgesia and stress response in elderly patients undergoing hip arthroplasty: a prospective randomized controlled double-blind trial.

BACKGROUND: As a novel regional analgesic technique, ultrasound-guided pericapsular nerve group (PENG) block has some potential advantages, and we designed a randomized clinical trial (RCT) to investigate whether the ultrasound-guided PENG block combined with general anesthesia can better reduce stress response, maintain intraoperative hemodynamic stability, and reduce postoperative analgesia in elderly hip arthroplasty compared with ultrasound-guided suprainguinal fascia iliaca block (SIFIB) combined with general anesthesia. METHODS: Seventy-four subjects were enrolled over an 8-month period (20 April 2023 to 31 December 2023). All patients were divided into the test group (group P) and the control group (group S) using the envelope as the randomization method. The test group was treated with preoperative ultrasound-guided PENG block analgesia combined with general anesthesia and the control group was treated with preoperative ultrasound-guided SIFIB analgesia combined with general anesthesia. The primary outcome selected was the patient Visual Analogue Scale (VAS) score at 12 h postoperatively. RESULTS: After generalized estimating equations (GEE) analysis, there was a statistically significant difference in the main effect of postoperative VAS score in group P compared with group S (P = 0.009), the time effect of VAS score in each group was significantly different (P < 0.001), and there was no statistically significant difference in the group-time interaction effect (P = 0.069). There was no statistically significant difference in the main effect of intraoperative mean arterial pressure (MAP) change (P = 0.911), there were statistically significant differences in the time effect of MAP in each group (P < 0.001), and there were statistically significant differences in the interaction effect (P < 0.001). CONCLUSIONS: In summary, we can conclude that in elderly patients undergoing hip fracture surgery, postoperative analgesia is more pronounced, intraoperative hemodynamic parameters are more stable, and intraoperative stress is less induced in patients receiving SIFIB than in patients receiving PENG block.

Intrinsic and extrinsic pathways of apoptosis induced by multiple antibiotics residues and ocean acidification in hemocytes of scallop Argopecten irradians irradians: An interactionist perspective.

The increasing prevalence of antibiotics in seawater across global coastal areas, coupled with the ocean acidification induced by climate change, present a multifaceted challenge to marine ecosystems, particularly impacting the key physiological processes of marine organisms. Apoptosis is a critical adaptive response essential for maintaining cellular homeostasis and defending against environmental threats. In this study, bay scallops Argopecten irradians irradians were exposed to multiple antibiotics (sulfamethoxazole, tetracycline, oxytetracycline, norfloxacin, and erythromycin, each at a concentration of 1 µg/L) combined with/without acidic seawater (pH 7.6) for 35 days. The single and interactive effects of the two stressors on apoptosis and the underlying mechanisms in hemocytes of A. irradians irradians were determined through flow cytometry analysis, comet assay, oxidative stress biomarkers analysis, and transcriptome analysis. Results showed that apoptosis could be triggered by either AM exposure or OA exposure, but through different pathways. Exposure to AM leads to mitochondrial dysfunction and oxidative damage, which in turn triggers apoptosis via a series of cellular events in both intrinsic and extrinsic pathways. Conversely, while OA exposure similarly induced apoptosis, its effects are comparatively subdued and are predominantly mediated through the intrinsic pathway. Additionally, the synergistic effects of AM and OA exposure induced pronounced mitochondrial dysfunction and oxidative damages in the hemocytes of A. irradians irradians. Despite the evident cellular distress and the potential initiation of apoptotic pathways, the actual execution of apoptosis appears to be restrained, which might be attributed to an energy deficit within the hemocytes. Our findings underscore the constrained tolerance capacity of A. irradians irradians when faced with multiple environmental stressors, and shed light on the ecotoxicity of antibiotic pollution in the ocean under prospective climate change scenarios.

Genetics and Epigenetics in the Genesis and Development of Microtia.

Microtia is a congenital malformation of the external and middle ear associated with varying degrees of severity that range from mild structural abnormalities to the absence of the external ear and auditory canal. Globally, it is the second most common congenital craniofacial malformation and is typically caused by inherited defects, external factors, or the interaction between genes and external factors. Epigenetics notably represents a bridge between genetics and the environment. This review has devoted attention to the current proceedings of the genetics and epigenetics of microtia and related syndromes.

Exploring Piezoelectric Actuation towards Its Applications in Laser Powder Bed Fusion Additive Manufacturing.

Piezoelectric materials, which exhibit a charge distribution across the surfaces in reaction to mechanical strain, find significant utility in actuation and sensing applications. Apart from actuation applications like acoustic devices, motors, and vibration damping, an emerging domain for ultrasonic actuators lies in additive manufacturing processes. Ultrasonic waves applied during solidification aim to modulate grain structure and minimize defects. This research focuses on a fixture designed to facilitate and optimize ultrasonic wave propagation through the build plate in laser powder bed fusion additive manufacturing by utilizing a piezoelectric transducer. Three implementations of piezoelectric transducers were evaluated based on their out-of-plane ultrasonic velocity transmissions. It was determined that a thin plate adhered to the surface of the piezoelectric transducer yielded the most favorable outcomes for implementation, achieving 100% transmission of velocity and energy. Preliminary analysis of melt pool morphology and defects in single-track laser scanning experiments demonstrated the impact of ultrasound on solidification, hinting at a novel approach to enhancing the printability of alloys in laser powder bed fusion additive manufacturing processes. The optimal fixture and the explored transducing efficiency could further guide advanced ultrasound testing to enable in situ defect and texture detection during the additive manufacturing processes.

A Fairness-Enhanced Federated Learning Scheduling Mechanism for UAV-Assisted Emergency Communication.

As the frequency of natural disasters increases, the study of emergency communication becomes increasingly important. The use of federated learning (FL) in this scenario can facilitate communication collaboration between devices while protecting privacy, greatly improving system performance. Considering the complex geographic environment, the flexible mobility and large communication radius of unmanned aerial vehicles (UAVs) make them ideal auxiliary devices for wireless communication. Using the UAV as a mobile base station can better provide stable communication signals. However, the number of ground-based IoT terminals is large and closely distributed, so if all of them transmit data to the UAV, the UAV will not be able to take on all of the computation and communication tasks because of its limited energy. In addition, there is competition for spectrum resources among many terrestrial devices, and all devices transmitting data will bring about an extreme shortage of resources, which will lead to the degradation of model performance. This will bring indelible damage to the rescue of the disaster area and greatly threaten the life safety of the vulnerable and injured. Therefore, we use user scheduling to select some terrestrial devices to participate in the FL process. In order to avoid the resource waste generated by the terrestrial device resource prediction, we use the multi-armed bandit (MAB) algorithm for equipment evaluation. Considering the fairness issue of selection, we try to replace the single criterion with multiple criteria, using model freshness and energy consumption weighting as reward functions. The state of the art of our approach is demonstrated by simulations on the datasets.

Engineered Design of a Mesoporous Silica Nanoparticle-Based Nanocarrier for Efficient mRNA Delivery in Vivo.

We have developed tailor-designed mesoporous silica nanoparticles (MSNPs) specifically for delivering mRNA. Our unique assembly protocol involves premixing mRNA with a cationic polymer and then electrostatically binding it to the MSNP surface. Since the key physicochemical parameters of MSNPs could influence the biological outcome, we also investigated the roles of size, porosity, surface topology, and aspect ratio on the mRNA delivery. These efforts allow us to identify the best-performing carrier, which was able to achieve efficient cellular uptake and intracellular escape while delivering a luciferase mRNA in mice. The optimized carrier remained stable and active for at least 7 days after being stored at 4 °C and was able to enable tissue-specific mRNA expression, particularly in the pancreas and mesentery after intraperitoneal injection. The optimized carrier was further manufactured in a larger batch size and found to be equally efficient in delivering mRNA in mice and rats, without any obvious toxicity.

Orientational Nanoconjugation with Gold Endows Marked Antimicrobial Potential and Drugability of Ultrashort Dipeptides.

Antibiotic resistance is a global threat. Antimicrobial peptides (AMPs) are highly desirable to treat multidrug-resistant pathogen infection. However, few AMPs are clinically available, due to high cost, instability, and poor selectivity. Here, ultrashort AMPs (2-3 residues with an N-terminal cysteine) are designed and assembled as gold nanoparticles. Au-S conjugation and ultrashort size restrict nonspecific reactions and peptide orientation, thus concentrating positively charged residues on the surface. The nanostructured assemblies enormously enhance antimicrobial abilities by 1000-6000-fold and stability. One representative (Au-Cys-Arg-NH2, Au_CR) shows selective antibacterial activity against Staphylococcus aureus with 10 nM minimal inhibitory concentration. Au_CR has comparable or better in vivo antimicrobial potency than vancomycin and methicillin, with low propensity to induce resistance, little side effects, and high stability (17.5 h plasma half-life). Au_CR acts by inducing collapse of membrane potential and rupture of the bacterial membrane. The report provides insights for developing AMP-metal nanohybrids, particularly tethering nonspecific reactions and AMP orientation on the metal surface.