ACS Publications最新文献

Choroidal neovascularization (CNV) represents a major cause of vision loss in various retinal diseases such as age-related macular degeneration (AMD). Current treatment involves frequent, often monthly, eye injections. The development of minimally invasive, long-term, painless, and effective ocular drug delivery systems is crucial for advancing the treatment of AMD. This study explores a novel method that integrates controllably bioresorbable silicon nanoneedles loaded with bevacizumab (Si NNs-Bev) on a tear-soluble subconjunctival patch for sustained, 1 year ocular drug delivery. The Si NNs-Bev embed into the sclera in a minimally invasive manner, undergoing controlled degradation over one year. This approach facilitates the sustained release of therapeutic agents, enhancing treatment efficacy and reducing treatment burden. Si NNs-Bev for the treatment of CNV are validated in a rabbit model of AMD. The SiNN-Bev patch achieved a sustained therapeutic effect on CNV regression, with a mean reduction of 82% by 4 months that is persistent for at least 1 year with minimal recurrence, which is consistent with the localized drug delivery mechanism facilitated by the transscleral microneedles. These preliminary findings underscore the potential of SiNNs as a platform technology for long-term, sustained ocular therapeutics.

Androgenetic alopecia (AGA) is the most common type of hair loss. Its successful treatment depends on effective transdermal drug delivery strategies. In this study, we introduce a novel method utilizing a controlled rigidity nanolipogel (NLG) for the local delivery of fucosterol in the treatment of AGA. The NLG is formed by an identical lipid bilayer encapsulating an alginate core, with rigidity regulated by the degree of sodium alginate (SA) cross-linking. Young's moduli obtained by AFM were 2.91 ± 0.41, 61.5 ± 1.6, and 84.9 ± 1.1 MPa for the soft NLP, moderately rigid NLG-2.5, and most rigid NLG-10. In vitro skin permeation study showed that compared with the NLP and NLG-10, NLG-2.5 had the best transdermal permeability and hair follicle-targeting properties. Moreover, moderately rigid NLG-2.5 exhibited the best ability to inhibit inflammation and androgen pathways and promote angiogenesis, thereby restoring hair growth in AGA model mice. This strategy provides valuable insights for the treatment of AGA.

Soilless cultivation relies on hydrogel matrices for water and nutrient management, but conventional hydrogels lose performance at low temperature and show unstable sustained release. Here this study develops an antifreeze sustained-release hydrogel (P-GTCH) that integrates l-proline (L-P) with a humic-acid-modified cellulose nanocrystal nanocomposite (CNCs-HA) for nanoenabled controlled release. L-P suppresses ice nucleation via hydrogen bonding, while CNCs-HA boosts HA loading and enables controlled transport within the cross-linked network. HA shows slow, continuous release governed by Fickian diffusion, achieving 96.7% cumulative release over 12 days at 0 °C and mitigating poor fertilizer release in cold environments. P-GTCH provides mechanical support for plant roots, and the synergistic effects of L-P and HA maintain lettuce germination above 86% at 0 °C while promoting root growth. This biobased, biodegradable platform is scalable for low-temperature soilless cultivation.

Enzymes such as oxidases are sustainable tools for hydrogel synthesis, but complex competing reactions have limited the mechanistic understanding and biomedical applications of these materials. Guided by molecular docking and MM-GBSA calculations, we identified two artificial substrates, desaminotyrosine (DAT) and desaminotyrosyltyrosine (DATT), that were experimentally more efficiently converted by mushroom tyrosinase (mTyr) than the natural substrate tyrosine. These substrates were used to synthesize hydrogels from DAT/DATT-functionalized star-shaped oligoethylene glycol (sOEG). Model reactions elucidated the chemical nature and functionality of the hydrogel netpoints. Material properties were systematically investigated depending on sOEG molecular weight (5, 10, 20 kDa), substrate type, and mTyr concentration. Functional mesh sizes and controlled release functions were investigated with fluorescent dextrans (4-500 kDa) and heparin. Cell culture studies with L929 fibroblasts and THP-1 monocytes suggested inertness of the material. These findings provide fundamental insight into mTyr-catalyzed hydrogel formation and support further exploration for in situ hydrogel synthesis.

Conventional gelatin-based hydrogel wound dressings suffer from weak mechanical properties, poor temperature stability, and slow wound healing, limiting their practical application. Herein, a novel multifunctional gelatin-based eutectogel dressing (PGEWD) was developed via a multicross-linked network constructed from porcine skin gelatin (PG), ε-polylysine (EPL), waterborne polyurethane (WPU), and deep eutectic solvent (DES, choline chloride-glycerol). DES induced PG molecular chain rearrangement to form a dense triple-helix structure. With the optimal formulation of 10% EPL, 0.3% WPU, and 10 min DES immersion, the PGE_0.1W_0.3D₁₀ composite exhibited high tensile strength (290 kPa), intrinsic conductivity (0.798 mS/cm), wide thermal tolerance (-20 to 60 °C), and ∼100% antibacterial activity. Combined with electrical stimulation (ES), it accelerated wound healing with ∼94.47% closure rate in 14 days. This study provides a versatile strategy for designing multifunctional gelatin-based wound dressings with significant potential in wound regeneration.

Liquid-liquid phase separation (LLPS) is involved in both the self-assembly of vital cellular organelles and the disease-associated protein misfolding, where LLPS precedes a liquid-solid phase transition (LSPT) leading to amyloid aggregates. Chimeric ACC_1-13K_n peptides are insightful models to study coupled LLPS/LSPT processes triggered by ATP-binding. Here, we investigated the impact of macromolecular crowding on the selection of the aggregation pathway in the ACC_1-13K₈-ATP system. While it has been previously shown that peptides with relatively short oligolysine segments (K₁₆ and shorter) skip the LLPS stage on their pathway to amyloid fibrils, we show here that concentrated polyethylene glycol (PEG), mimicking intracellular crowding conditions, induces prior formation of liquid droplets that subsequently facilitate fibril formation. The influence of PEG contrasts with the behavior of other types of macromolecular crowding agents, Dextran and Ficoll, which accelerate aggregation without a detectable LLPS phase, and that of serum albumin, which prolongs the nucleation phase. In the presence of PEG-induced macromolecular crowding, the fibrillization in the ACC_1-13K₈-ATP system appears to reach a maximal rate limited by diffusion coupled to the conformational dynamics of the polypeptide chains within the droplets. Importantly, the ACC_1-13K₈-ATP fibrils formed in the presence of PEG are distinct from those of the ACC_1-13K₈-ATP amyloid formed in the absence of crowding in terms of their infrared characteristics, morphological features, and overall stability. Our findings suggest that macromolecular crowding can switch between kinetically and thermodynamically favored amyloid polymorphs and that the chemical properties of the crowding agents are key factors in their impact on protein aggregation processes. The results are discussed in the context of the mechanisms of LLPS-dependent protein misfolding and amyloid formation.

Therapeutic interventions for complex diseases depend on the targeted modulation of key pathological pathways. While growing clinical needs continue to drive advancements in the drug discovery space, current strategies primarily rely on searching large volumes of chemical data without addressing the specific contributions of molecular features. Moreover, both clinicians and researchers recognize the need for improved drug discovery methods and characterization that could aid in clinical strategy selection. To address these challenges, we propose a new perspective on targeted therapy development as well as interactome mapping, utilizing molecular fragments. The present study focuses on therapeutic areas that represent emerging targets, namely JAK2 and GLP-1R, both of which have broad clinical potential. We developed a new self-adjusting neural network that enabled us to discover novel therapeutic candidates with improved in silico binding profiles, gain additional insights into drug-target binding that were not previously reported, and identify new metabolic trajectories. Importantly, our work revealed that even a small compound library can effectively generate lead candidates, expediting the search and exploration process. In addition, the fragment-guided bridging of chemical and biological spaces has revealed new opportunities for drug repurposing efforts and a means of improving the prediction of side effects. We concluded our study with insights into the recent high-profile clinical trial failure of danuglipron and how this could have been prevented with our methodology. Thus, building a robust in silico pipeline with integrated screening data can significantly reduce costs and guide therapy adoption. Furthermore, our proposed strategy highlights promising avenues for the discovery of new therapeutics and the development of clinical interventions.

Infantile-onset Ascending Hereditary Spastic Paralysis (IAHSP) is an ultrarare, autosomal recessive form of Hereditary Spastic Paraplegia (HSP), caused by mutations in the ALS2 gene, which encodes the protein ALSIN. In a previous study, we proposed a personalized therapeutic strategy for an Italian IAHSP patient (AO), aiming to correct the aberrant function of the R1611W mutant ALSIN using Menatetrenone (MK4). While our results supported compassionate-use approval for a patient-specific therapeutic regimen, further investigation was needed to highlight the treatment's benefits in the absence of tractable biophysical assays and in vivo models. In this respect, we first characterized MK4's interaction with the mutation site through Molecular Dynamics simulations. Next, we established and characterized a skin fibroblast cell line derived from patient AO. We analyzed the expression and stability of the mutant ALSIN protein in AO's fibroblasts and observed elevated oxidative stress levels. Using advanced microscopy and automated image analysis, we identified a characteristic mitochondrial phenotype associated with AO's IAHSP. One specific morphological parameter of mitochondria (Mean Branch Diameter) accurately reflected the IAHSP phenotype and was selected as a cell marker. Treatment of IAHSP fibroblasts with MK4 highlighted the rescue of Mean Branch Diameter and ALSIN levels, supporting cellular efficacy. Overall, this work presents an approach that integrates computational and cell-based methodologies to overcome the data scarcity challenges of drug discovery in rare diseases. Our study provides a framework for preclinical, alternative drug discovery programs in monogenic rare disorders such as IAHSP.

Carbon black (CB) and silica are the most widely used reinforcing fillers for rubber composites. However, their molecular-scale surface differences and quantitative effects on interfacial interactions remain unclear, hindering the rational design of high-performance materials. In this study, CB- and silica-filled composites with equivalent interfacial areas were prepared to experimentally compare their interfacial interaction strengths. Molecular dynamics simulations using trans-3-hexene as probe molecules subsequently quantified the interaction strengths of CB and silica, showing good agreement with the experiments. Further analyses of surface energy distribution and the dependence of binding energy on adsorption distance revealed that the molecular-scale surface characteristics differ in three key aspects: adsorption energy, energy heterogeneity, and binding energy-distance correlation, thereby accounting for the inferior performance of silica-NR interfaces despite the presence of covalent bonding. On the basis of the simulation results, experiments under equivalent interfacial adsorption energies confirmed that interfacial physical adsorption dominates the overall interfacial interactions and validated the critical role of specific strong binding sites. In this study, an efficient molecular simulation methodology was established to overcome experimental limitations, and by integrating simulations with experiments, the influence of filler surface characteristics on interfacial interactions was elucidated, providing guidance for rational composite design.

Coke deposition is a key obstructive problem to be solved in the production of ethylene via steam cracking; moreover, the removal of graphitic carbon in coke is particularly difficult. A strategy integrating Fe-Mn bimetallic synergy at the B-site with oxygen vacancy engineering in perovskites was proposed to accelerate the catalytic conversion of coke/graphitic carbon via steam. DFT simulations and experimental results revealed that Mn incorporation induces dynamic lattice reconstruction of SrFeO₃, generating abundant oxygen vacancies that enhance oxygen ion mobility and H₂O adsorption. The interaction between Fe and Mn atoms has been observed to narrow the band gap, strengthen the hybridization of the O-2p and Fe-3d orbitals, induce electron delocalization, regulate the transfer of electrons from surrounding atoms to the adsorbed oxygen species, and thus accelerate the desorption and activation of *OH and the transfer of *O^2-, which provides the possible reaction pathway for the transformation of graphitic carbon into CO or CO₂. At 900 °C, the conversion of graphitic carbon and coke with steam catalyzed by SrFe_0.1Mn_0.9O₃ reached 60.61% and 99.87%, respectively. This study provides an active material that facilitates the in situ online decoking strategy for catalytic coatings on steam cracking furnace tubes along with theoretical insights into the underlying reaction mechanism.