Aggregate (Hoboken, N.J.)最新文献

Protein aggregation drives proteinopathies ranging from ALS to systemic amyloidosis, yet the multiscale determinants bridging sequence, structure, and kinetics remain elusive. We present SKALE, an interpretable machine learning framework that integrates sequence motifs, AlphaFold-derived structural descriptors, and experimental kinetics to decode aggregation mechanisms. SKALE identifies latent hotspots that evade conventional tools and matches high-performing neural baselines while preserving computational efficiency. In ALS-linked SOD1 G86R, the model isolates a risk region at residues 72–91 where preserved β-sheet geometry coincides with weakened hydrogen bonding to drive nucleation. Similarly, analysis of TDP-43 S332N reveals that a locally unwound helix increases surface exposure, a prediction validated by showing that targeted deletion of model-identified regions significantly reduces cellular aggregation. The framework generalizes to Tau P301L and PRNP variants where it uncovers distal aggregation-prone regions to discriminate pathogenic drivers from neutral mutations. Interpretability analysis further disentangles global from mutation-local mechanisms to reveal that β-sheet propensity acts as a shared determinant while hydrogen bond dynamics define specific routes to nucleation. These findings establish SKALE as a scalable, disease-agnostic engine that combines high-fidelity prediction with biophysical resolution to decode the molecular logic of misfolding and guide therapeutic design.

Nanozymes, a promising class of enzyme mimics based on nanostructures, have attracted considerable research interest. However, in sharp contrast to the structural precision of natural enzymes, most nanozymes are poorly defined structurally. The absence of nanozyme systems that mimic natural isoenzymes—which catalyze similar reactions despite slight differences in their chemical structures—has particularly hindered the understanding of their structure–performance relationships. Such nanozyme analogues, termed iso-nanozymes, remain largely unexplored. Here, we report the first pair of iso-nanozymes. Two analogous copper nanoclusters—[Cu₃₂(SC₂H₅)₁₆(PPh₃)₈Cl₉]⁺ (Cu₃₂) and [Cu₃₀(SC₂H₅)₁₆(PPh₃)₆Cl₉]⁺ (Cu₃₀)—were synthesized and structurally characterized. Single-crystal X-ray diffraction analysis reveals that Cu₃₀ possesses an identical metal framework and ligand types as Cu₃₂, with a comparable ligand distribution. The only structural difference is the absence of two PPh₃Cu⁺ units in Cu₃₀, which results in a substantial enhancement of its catalytic performance in the horseradish peroxidase-mimicking reaction. Under identical conditions, the specific activity (SA) of the Cu₃₀ nanozyme is approximately 6.5 times higher than that of Cu₃₂. Density functional theory calculations indicate that the notable difference in the SA between the two cluster nanozymes is attributed to variations in adsorption energies, which stem from their different geometric and electronic structures. This study not only introduces the novel concept of iso-nanozymes using atomically precise metal nanoclusters, but also establishes a model system for investigating the critical influence of nanozyme structure, down to the atomic level, on catalytic efficiency. These findings are anticipated to inspire further research interest in atomically precise metal nanoclusters within the nanozyme community.

Peptide- and drug-protected gold nanoclusters (Au NCs) with atomic precision have attracted research attention in the last few years owing to their ultrasmall size (<2 nm), well-defined structures, tunable photoluminescence from the visible to near-infrared range, water solubility, and good biocompatibility. These features, combined with low toxicity and efficient renal clearance, make such Au NCs promising candidates for biomedical use, including diagnosis, therapy, and theranostic. The incorporation of peptides or drugs into Au NCs enhances the stability, targeting specificity, cellular uptake, and prolonged circulation, enabling precise modulation of biological responses. Despite notable advances in achieving atomic precision employing complex ligands such as peptides or drugs, the synthetic methods of this new class of NCs remain a challenge. Careful control of molar ratio (Au: peptide/drug), reducing agent, temperature, and reaction time is required, because these factors directly influence the cluster size, optical properties, and in vivo performance. In this review, we highlight different synthetic approaches of atomically precise peptide- and drug-protected Au NCs, emphasizing the role of rational ligand design and reaction conditions, as well as the challenges associated with structural determination. We further discuss the optical and photoluminescence properties of peptide-protected Au NCs—the mostly explored features for biomedical applications. Finally, we conclude by outlining the current challenges, opportunities for scale-up synthesis, and future design perspectives for these emerging nanomaterials.

Atomically precise silver nanoclusters (AgNCs) offer unique opportunities to correlate structure and photophysical properties, yet enhancing their photoluminescence emission remains challenging due to dominance of non-radiative decay pathways. Here, we report a ligand-engineering strategy to modulate the optical properties of high-nuclearity Ag₅₆ NCs. The synthesized two NCs, Ag₅₆S₁₂(^tBuS)₂₀(CF₃CO₂)₁₂(MeCN)₃ (NC-I) and Ag₅₆S₁₂(^tBuS)₂₀(ⁿBuSO₃)₁₂ (NC-II), possess a similar hexagonal-close-packed Ag₁₄ kernel, which is encapsulated by a similar icosahedral S₁₂ middle-shell and an outer Ag₄₂ shell, but differ in overall symmetry and outer Ag-ligand shell connectivity. Replacement of bidentate CF₃CO₂⁻ with tridentate ⁿBuSO₃⁻ ligands increases overall Ag─X (X = O, S, and Ag) bonding interactions, resulting in not only a more rigid and compact outer Ag₄₂ shell structure but also contraction of cationic Ag₁₄ core and anionic icosahedral S₁₂ middle-shell. These structural modifications enhance radiative decay and suppress non-radiative pathways, leading to a 17-fold increase in photoluminescence quantum yield and extended average emission lifetime. Computational analysis confirms that ligand-induced geometric stabilization and electronic delocalization govern the excited-state dynamics. This work demonstrates that rational ligand design can synergistically tune cluster geometry, rigidity, and electronic structure, providing a general strategy to improve the photophysical performance of high-nuclearity AgNCs.

The electrochemical reduction of CO₂, as a renewable energy-driven electrochemical system, has emerged as an environmentally benign approach for producing valuable chemicals and fuels under mild reaction conditions. Recent advances in the precise synthesis of metal nanoclusters, coupled with state-of-the-art characterization techniques, have enabled atomic-level investigation of structure–activity relationships in nanocatalysts. Due to their well-defined atomic architectures, the active metal sites within these nanocatalysts can be accurately identified, facilitating systematic studies on how compositions (structures) modulate catalytic performance. This review begins by summarizing recent advances in the controlled synthesis of atomically precise metal nanoclusters, followed by an overview of progress in the electrochemical reduction of CO₂ to CO using nanoclusters as catalysts. Subsequently, we systematically investigate the effects of metal kernel characteristics and staple properties on catalytic activity, selectivity, and stability. Furthermore, current challenges are outlined, and prospective research directions are proposed in this rapidly evolving field. It is anticipated that this review will inspire further innovation in the synthesis of atomically precise nanocluster catalysts, promote a deeper mechanistic understanding of metal nanocluster-mediated electrochemical CO₂ reduction, and push forward the related industrial applications.

Copper is one of the most abundant and less toxic transition metals in nature, which exhibits rich oxidation states and versatile catalytic activity using O₂ as an oxidant. To date, enormous efforts in crystallographic and spectroscopic analyses have explicitly disclosed the pivotal role of polynuclear copper aggregates in the biological and organocatalytic redox processes. Notably, most biological Cu–O active sites often have unsymmetrical coordination environments for each copper ion, which finally account for the differentiated redox properties and biological functions. Inspired by the structural biology advances, numerous synthetic model complexes as enzyme mimics and organocatalytic active species have been established to identify enzymatic reaction intermediates and clarify the catalytic mechanisms. However, those synthetic models often show identical or similar coordination environments for individual copper ions because of the extensive application of synthetically accessible symmetrical ligands. In this Perspective, we endeavor to summarize the composition and structural details of Cu–O active species in several important copper-containing enzymes and pay special attention to the coordination environments of individual copper ions therein. Mechanistic studies on the biased functions of individual copper centers and the cooperative effect among them have been comprehensively surveyed. Recent progress of the synthetic Cu–O model complexes with unsymmetrical coordination environments, including the distinctive bi-cluster [alkynyl–copper–oxygen] aggregate, is discussed in detail to clarify the distinctive structure–property relationship of nonequivalent copper ions. We hope that this Perspective reiterates the unsymmetrical structural features of polynuclear copper aggregates in copper-catalytic systems and highlights the unique effect of coordination unequivalence in redox process, and provides new inspiration for the rational design of novel multimetallic catalysts.

As a vital component of innate immunity, the cGAS-STING pathway has attracted widespread attention in cancer therapy, among which Mn²⁺ has emerged as a promising antitumor agent. Combining cGAS-STING agonists with chemotherapy or cancer vaccines represents an effective strategy to enhance their therapeutic efficacy. In this study, we construct simple manganese chloride nanosheets (MnCl₂ NSs) that achieve combined effects resembling those of cGAS-STING activation, chemotherapy, and in situ vaccination without requiring additional drugs or energy input. The synthesized MnCl₂ NSs release high concentrations of Mn²⁺ into tumor cells, causing a storm of Mn²⁺. Through the combined effects of osmotic pressure, chemodynamic therapy (CDT), and cGAS-STING activation, they significantly enhance the cytotoxicity of MnCl₂ and induce DNA damage, thereby achieving chemotherapy-like combined therapeutic effects. Concurrently, tumor cells undergo PANoptosis, leading to the release of damage-associated molecular patterns (DAMPs) and tumor antigens, which effectively generate an in situ tumor vaccine, ultimately activating both innate (cGAS-STING) and adaptive (PANoptosis) immune responses. Our study proposes a novel strategy to synergistically enhance immunotherapy by inducing tumor cell PANoptosis while concurrently activating the cGAS-STING pathway, offering valuable guidance for the design of immunotherapeutic nanomaterials.

Although alkyne-based polymerizations have significant potential for advanced materials, achieving efficient and spatiotemporally controlled polymerizations under mild, additive-free conditions remains a challenge. In this work, we report a facile light-induced click polymerization between activated alkynes and 2-methylbenzaldehydes (o-MBAS). This polymerization can be completed within 1 h at room temperature without any catalysts or additives, and features high atom economy, spatiotemporal controllability, and operational simplicity. Under optimized conditions, a series of soluble and thermally stable poly(naphthalene)s, poly(anthracene), and poly(phenanthrene) with high molecular weights (M_w up to 46,800 Da) were obtained in excellent yields (up to 99%). The resulting polymers exhibit outstanding photophysical properties. The poly(anthracene) can specifically label lipid droplets in cells. In addition, introducing the tetraphenylethylene (TPE) moiety into the polymer backbones endows the resultant polymers with unique aggregation-induced emission (AIE) properties, enabling the preparation of fluorescent patterns. Moreover, the precise spatiotemporal nature of this polymerization also supports the fabrication of well-defined 2D and 3D polymer architectures. This work not only expands the scope of alkyne-based polymerizations but also provides a useful and flexible platform for the spatiotemporally controlled synthesis of polymers.

The Aβ peptide contributes to Alzheimer's disease through various mechanisms, including cell membrane disruption. While the fibrillar structure of Aβ_1–42 in aqueous medium has been elucidated, its oligomer structure remains elusive. We have combined Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), solid-state NMR (ssNMR), and molecular dynamics (MD) approaches to achieve a structural model for Aβ_1–42 octamer in lipid bilayers. FTIR data identify conformational transitions of Aβ_1–42 to a stable β-sheet structure. ssNMR analysis allows assignment of 38 out of 42 Aβ_1–42 residues, with three additional inter-residue contacts to define the tertiary fold. Combined, MD simulations produce a structural model of Aβ_1–42 octamers in a novel sushi-roll fold of in-register cross-β motif with a lipid-filled internal cavity. The membrane-embedded structure of Aβ_1–42 and the mode of peptide-lipid interactions provide a better understanding of Aβ neurotoxicity.