ACS Publications最新文献

The low cure rate and high mortality associated with cancer pose significant threats to human health. Photodynamic and photothermal therapies have emerged as promising treatment strategies for various types of cancers. In this study, we successfully synthesized a novel type of carbon dot (CD) using 1,2,4-aminobenzene and ethylenediamine as precursors. Surprisingly, these CDs exhibited outstanding nucleolus-targeting capabilities coupled with a remarkable photothermal effect. Through the integration of these nucleolus-targeting CDs with indocyanine green (ICG) and folic acid (FA), we created CDs-ICG-FA nanocomplexes suitable for combined photodynamic and photothermal therapy. In vitro experiments demonstrated that CDs-ICG-FA maintained a robust photothermal ability, achieving a conversion efficiency of up to 34.3%. Furthermore, CDs-ICG-FA generated abundant reactive oxygen species, effectively inducing cancer cell death and demonstrating its potential for photodynamic therapy. In MCF-7 cancer cells, CDs-ICG-FA exhibited a pronounced synergistic photothermal/photodynamic anticancer effect. Subsequent in vivo experiments in mice revealed that CDs-ICG-FA could selectively accumulate at tumor sites, significantly inhibiting tumor growth upon exposure to an 808 nm laser. These findings suggest that the developed nucleolus-targeting CDs-ICG-FA hold promising potential for cancer targeting and the application of combined photothermal/photodynamic therapy.

Microneedles (MNs) are emerging as versatile tools for both therapeutic drug delivery and diagnostic monitoring. Unlike hypodermic needles, MNs achieve these applications with minimal or no pain and customizable designs, making them suitable for personalized medicine. Understanding the key design parameters and the challenges during contact with biofluids is crucial to optimizing their use across applications. This review summarizes the current fabrication techniques and design considerations tailored to meet the distinct requirements for drug delivery and biosensing applications. We further underscore the current state of theranostic MNs that integrate drug delivery and biosensing and propose future directions for advancing MNs toward clinical use.

It is well known that impaired wound healing associated with diabetes mellitus has led to a challenging problem as well as a global economic healthcare burden. Conventional wound care therapies like films, gauze, and bandages fail to cure diabetic wounds, thereby demanding a synergistic and promising wound care therapy. This investigation aimed to develop a novel, greener synthesis of a laser-responsive silver nanocolloid (LR-SNC) prepared using hyaluronic acid as a bioreductant. The prepared LR-SNC was embedded into a stimuli-responsive in situ gel (LR-SNC-in situ gel) for easy application to the wound region. The physicochemical characterization of LR-SNC revealed a nanometric hydrodynamic particle size of 25.59 ± 0.72 nm with an -31.8 ± 0.7 mV surface ζ-potential. The photothermal conversion efficiency of LR-SNC was observed up to 62.9 ± 0.1 °C. In vitro evaluation of LR-SNC with and without NIR laser irradiation exhibited >70% cell viability, confirming its cytocompatibility for human keratinocyte cells. The in vitro scratch assay showed significant wound closure of 75.50 ± 0.02%. Further, the addition of cytocompatible LR-SNC into an in situ gel followed by laser irradiation resulted in substantial in vivo wound closure (86.69 ± 2.48%) in a diabetic wound-bearing mouse. Histological evaluation demonstrated salient features of the healed wounds, such as increased neovascularization, collagen density, migration of keratinocytes, as well as growth of hair follicles. Additionally, the findings showed a decrease in the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and enhanced angiogenesis gene expression (VEGF and CD31), thereby healing the diabetic wound efficiently. The present study confirmed the potential role of silver nanocolloids followed by laser irradiation in treating diabetic wound mouse models.

Ligand-conjugated small interfering RNAs (siRNAs) have emerged as a powerful approach to developing nucleic acid-based medicines. To achieve efficient mRNA knockdown, it is important to select targeting receptors with high expression and ligands that exhibit rapid internalization. However, the key characteristics of ligand-receptor sets involved in the postinternalization process remain largely unclear. In this study, we investigated the effect of ligand-receptor binding dissociation under low pH conditions, known as a postendocytic environment. Specifically, we chemically synthesized several modified epidermal growth factor (EGF) ligands that showed a variety of binding activities to the EGF receptor (EGFR) at low pH. Among these modified ligands, the siRNA conjugate with chemically synthesized EGF H10Y/H16Y, which is a less pH-responsive variant, exhibited reduced internalization and mRNA knockdown activity at high concentrations in EGFR-expressing cells. Additionally, we explored the use of antibody-related molecules (anti-EGFR IgG and Fab) as targeting moieties for siRNA conjugates. The anti-EGFR Fab-siRNA, which showed dissociation of EGF under low pH conditions, demonstrated stronger internalization and mRNA knockdown activity compared to the anti-EGFR IgG-siRNA, which strongly binds EGF at low pH. These data emphasize the importance of intracellular ligand-receptor dissociation and provide insights for future advancements in the field.

Near-interfacial electrons in water can be produced by bombarding an aqueous microjet in vacuum with gas-phase sodium atoms. These Na atoms immediately ionize into Na⁺ and e_s^-, which can then react with surface-active molecules that preferentially populate the surface. We carried out these experiments by reacting e_s^- with the surfactant benzyltrimethylammonium (BTMA⁺) in a 6.7 M LiBr/H₂O microjet at 242 K as a function of pH between 1 and 5. The reaction products, trimethylamine (TMA) and benzyl radical, evaporate into the gas phase where they are detected by a mass spectrometer. We find that TMA evaporation sharply diminishes with increasing H⁺ concentration and is barely visible at pH = 1, while benzyl evaporation varies much less. These results indicate that TMA protonation overwhelms TMA evaporation at 0.1 M H⁺. Diffusion-reaction modeling matches the observed trends and predicts that e_s^- reacts with BTMA⁺ within the top 20 Å at all pH values. However, TMA molecules that evaporate and escape protonation diffuse on average only over 20 Å at pH = 1 but over 1000 Å at pH = 5. These observations emphasize that the near-interfacial region provides a controllable reaction environment that is also an escape route for volatile intermediates, a route that is unavailable deep in the bulk. The competition between evaporation and reaction depends on the solubility of the intermediate, the location of its creation, and the propensity for secondary reactions.

Lyophilization remains a key method for preserving sensitive biopharmaceuticals such as monoclonal antibodies. Traditionally, stabilization mechanisms have been explained by vitrification, which minimizes molecular mobility in the lyophilized cake, and water replacement, which restores molecular interactions disrupted by water removal. This study proposes a novel design strategy that combines water activity and glass-transition temperature as the main indicators to predict long-term stability in lyophilized formulations. The water activity, calculated as the product of water activity coefficient and (residual) water content, serves as a mutual indicator of molecular interactions and influence of residual water content in the lyophilizate. By predicting beneficial excipient combinations through activity coefficient calculations using the perturbed-chain statistical association fluid theory model and calculating T_g using the Gordon-Taylor equation, the study identifies favorable excipient systems, such as sucrose/ectoine mixtures, providing formulation windows that offer broad stability ranges. The approach was validated with stability studies, confirming that formulations within a water activity range of 0.025-0.25 exhibit high (long-term) stability. This work advances formulation development by integrating water-excipient interactions and residual moisture content into a predictive model, moving beyond traditional empirical methods and offering a robust pathway to the design of stable biopharmaceutical formulations. This makes it possible to achieve high/favorable water activities despite low residual moisture (thus, high glass-transition temperatures) with plausible excipient concentrations and combinations.

The development of nanodrugs targeting multidrug-resistant bacteria, while sparing the beneficial constituents of the microbiome, has emerged as a promising approach to combat disease and curb the rise of antimicrobial resistance. In this investigation, we devised a siderophore-functionalized nanodrug based on a gold nanoparticle construct (AuNP-NSC; Gold nanoparticle_N-heterocyclic_Siderophore_Cyanine7), offering an innovative treatment modality against drug-resistant bacterial pathogens. As a proof of concept, the efficacy of this nanodrug delivery and antimicrobial therapy was evaluated against the notoriously resistant bacterium P. aeruginosa. N-Heterocyclic carbenes (NHCs) exhibit a strong affinity for transition metals, forming highly stable complexes resistant to ligand displacement. The entry of siderophore-conjugated nanodrugs into bacteria is facilitated through specific receptors on the outer membrane. In our study, AuNP-NSC was specifically targeted and imported into resistant Gram-negative P. aeruginosa via binding with ferric iron. Treatment with the developed nanodrug significantly inhibited the proliferation of antibiotic-resistant P. aeruginosa, reducing bacterial counts by more than 95% and mitigating drug resistance. Furthermore, AuNP-NSC markedly diminished P. aeruginosa-induced skin lesions and forestalled systemic organ failure triggered by secondary sepsis in mouse models. These findings underscore the potential of nanodrugs as specialized therapeutic agents for the management of antibiotic-resistant bacterial infections.

Hydrogels have emerged as promising candidates for flexible sensors due to their softness, biocompatibility, and tunable physicochemical properties. However, achieving synchronous satisfaction of conformality, conductivity, and diverse biological functions in hydrogel sensors remains a challenge. Here, we proposed a multifunctional hydrogel sensor by incorporating silver-loaded polydopamine nanoparticles (Ag@PDA) into a thermally cross-linked methacrylamide chitosan (CSMA) and acrylamide network, namely, Ag@PDA/(CSMA-PAM). The Ag@PDA/(CSMA-PAM) hydrogel showed the capability to respond effectively to both strain and pressure, enabling its independent application as either a strain sensor or a pressure sensor. The sensitivity of the hydrogel can reach 2.13 within the strain range of 65 to 150%, exhibiting a response and recovery time of 550 ms when utilized as a strain sensor. In contrast, its sensitivity was 0.07 kPa^-1 during pressures ranging from 0 to 2.15 kPa, with a response and recovery time of 136 ms when employed as a pressure sensor. Additionally, the hydrogel sensor demonstrated high linearity (0.998 for strain and 0.98 for pressure), stable cycling ability (500 cycles), and low detection limit (0.5% for strain and 150 Pa for pressure). Moreover, the Ag@PDA/(CSMA-PAM) hydrogel exhibited good stability and reliability for a variety of practical applications, including the detection of subtle and large deformations, as well as real-time physiological activity monitoring. Further, owing to the bioactive components of chitosan and Ag@PDA present in the hydrogel, the Ag@PDA/(CSMA-PAM) sensor exhibited satisfactory biocompatibility along with excellent antioxidant and antibacterial activities, making it highly promising for applications as wearable sensors in personalized healthcare.

Rho-associated protein kinase (ROCK) inhibitors are promising therapeutic agents for reducing elevated intraocular pressure in patients with glaucoma. We explored new ROCK inhibitors derived from bioactive metabolites produced by microbes, specifically cryptic metabolites from Nocardiopsis sp. MCY7, using a liquid chromatography-mass spectrometry-based chemical analysis approach integrated with metal stress-driven isolation. This strategy led to the identification of two previously undescribed linear peptides, nocarnickelamides A and B (1 and 2), and an unreported cittilin derivative, cittilin C (3). The planar structures of 1-3 were elucidated using UV spectroscopy, high-resolution mass spectrometry, and nuclear magnetic resonance. The absolute configurations of 1 and 2 were assigned using the advanced Marfey's method. Biological assays demonstrated that nocarnickelamides (1 and 2) exhibited dual inhibitory activity against ROCK1 (IC₅₀ 29.8 and 14.9 μM, respectively) and ROCK2 (IC₅₀ 27.0 and 21.9 μM, respectively), with molecular simulations suggesting binding to the ATP-binding site. In human trabecular meshwork cells, 2 significantly inhibited the activation of ROCK-regulated cytoskeletal contraction markers such as the myosin light chain. Nocarnickelamide B (2) is a novel dual ROCK1/2 inhibitor and a potential pharmacophore for designing new therapeutic agents to reduce intraocular pressure in glaucoma.

The chemical forms and transport properties of thorium and uranium ions in molten LiF-BeF₂ are systemically studied via first-principles molecular dynamics simulations. The densities, diffusion coefficients, densities of electronic states, and ionic pair and cluster structures of molten LiF-BeF₂-ThF₄ (FLiBeTh), LiF-BeF₂-UF₄ (FLiBeU), and LiF-BeF₂-ThF₄-UF₄ (FLiBeThU) are analyzed in detail. Studies have shown that the density and thermal expansion coefficient of molten FLiBeTh are higher than those of FLiBeU in the temperature range of 873-1073 K. Besides, FLiBeTh has higher electron energy, and the active Th electrons contribute to the diversification of its coordination structure and the improvement of diffusion property. Furthermore, the concept of Be-F tetrahedron stress index (SIT) is proposed in molten FLiBe, and the higher SIT of molten FLiBeU is one of the structural factors leading to slow diffusion coefficients of Be and F ions. Overall, the understanding and characterization of fuel salt structure and property are underscored, and the relationships between microstructure and diffusivity performance are preliminarily established.