ACS Publications最新文献

Colorectal cancer (CRC) is the second leading cause of death in the United States in the adult population. When detected at early stages, the survival rate is higher than 70% but when diagnosed at a metastatic stage, the 5-year survival rate significantly declines to 15%. In recent years, immunotherapy has shown promising results in a selective patient population with advanced or metastatic CRC with microsatellite instability (MSI) and mismatch repair (MMR). Hydrogels are a growing field of research to improve the delivery of monoclonal antibodies. In this work, a gellan gum-based (GG) hydrogel noncovalently cross-linked using trilysine (TLA) was characterized for its drug release and diffusion properties. A partial release of the checkpoint inhibitor anti-programmed death-1 (aPD-1) was observed with an almost 40% cumulative release within the first 24 h. FRAP analysis showed varying diffusion rates (μm²/s) for Atto 488-IgG (2.63 ± 0.32), 60-76 kDa FITC-Dextran (2.65 ± 0.31), and 150 kDa FITC-Dextran (2.80 ± 0.83), with a 70-90% recovery postbleaching. Additionally, intratumoral delivery of aPD-1 was evaluated in a CRC mouse (C57BL/6) tumor model inoculated with MC38 cells. Quantification of aPD-1 in the plasma and tumor showed an increase in concentration by 1.5- and 3-fold, respectively, when delivered using the intratumoral hydrogel route in comparison with either intraperitoneal (i.p.) or drug-free intratumoral administration. Overall, this noncytotoxic hydrogel provided an alternative delivery route for aPD-1, maximizing its presence both in circulating blood and in the treatment site, serving as a simple localized delivery system in CRC.

Although HPV vaccines currently in use with aluminum adjuvants demonstrate significant stimulation of humoral immunity, the weak cellular immune response that they elicit indicates a need for further improvement. On the other hand, not only the poor immune promotion effect inducted by a single adjuvant but also finding an efficient antigen and adjuvant codelivery carriers need to be addressed. Here, a double Toll like receptor agonist (R848, Poly(I:C)) and antigen of HPV16 L1 pentamer were codelivered by using calcium phosphate (CaP) mineralized PLGA microparticles. The results of in vivo experiments indicate that the secretion of specific antibodies and neutralizing antibodies was significantly increased, and T/B cells in lymph nodes were effectively activated. Of particular note is the formation of more germinal centers in vivo stimulated by the formulation. In addition, the cellar immunity is also promoted with a higher level of cytokines secretion as IFN-γ, TNF-α, and IL-12p70. Therefore, the as-prepared formulations are a potential platform for preventing the HPV virus infection.

The use of generative machine learning models, trained on the experimentally resolved structures deposited in the protein data bank, is an attractive approach to sampling conformational ensembles of proteins. However, the ensembles generated by these models lack time scale or causal information. We use the structural ensembles generated from AlphaFold2 at a range of MSA depths to parametrize the potential of mean force of an overdamped, memory-free, coarse-grained Langevin equation. This approach couples the AlphaFold2 ensembles to a causal model, allowing us to estimate the time scales spanned by the ensembles generated at each MSA depth. Performing this analysis on six variants of HIV-1 protease, we confirm an inverse relationship between MSA depth and the time scale of an ensemble's conformational fluctuations. The MSA depth essentially serves as a conformational restraint, and AlphaFold2 is generally able to probe time scales at or below those seen in microsecond-long, unbiased molecular dynamics simulations. We conclude by generalizing this approach to other generative structural ensemble-prediction methods as well as cofolding models, in this case, the biologically functional HIV-1 protease dimer.

The integration of excellent performance and facile closed-loop recycling of poly(butylene terephthalate) (PBT) copolyesters remains a significant challenge. Herein, a biobased rigid diol (denoted as HT) was prepared by an acid-catalyzed acetalization reaction from 5-hydroxymethylfurfural (HMF) and trimethylolpropane (TMP). HT was copolymerized with PBT to prepare a series of PBT_xTT_y copolyesters with high M_n up to 45.5 kDa. The insertion of HT led to excellent thermomechanical and UV shielding properties, such as the glass transition temperature (T_g of 47.3 °C) and strength (43 MPa) of PBT₈₀TT₂₀ outdistancing those of PBT. More importantly, the acetal-based HT enabled dual closed-loop recycling pathways for PBT_xTT_y copolyesters via selective cleavage of acetal or ester bonds, allowing the recovery of structures terminated with aldehyde/hydroxyl end groups or PBT. Both recycled products could be repolymerized. Overall, HT is an effective biobased precursor that can prepare PBT-based copolyesters with excellent physical properties and dual closed-loop recyclability.

Molecular self-assembly creates complex structures through noncovalent interactions. Synthetic fuel-driven systems mimic biology, yet the effects of subtle design changes, particularly hydrophobic groups such as alkyl chains, are still not well understood. This study showed that the alkyl chain length critically influences the dynamic assembly of short peptides. Z-capped peptides C3 and C6, composed of l-phenylalanine and -glutamic acid, with L-aspartic acid as the reactive site and alkylamide groups of varying lengths at the C-terminus, have been observed to form metastable aggregates via intramolecular anhydride formation during a chemically fueled reaction cycle. We elucidated that the difference in alkyl chain length resulted in either highly dynamic assemblies or delayed structural dissolution. Our findings provide a comprehensive understanding of these observations, illustrating how rational peptide design enable precise control over nanostructure properties and catalytic lifetimes.

Elastin-like polypeptides (ELPs) are a family of recombinant biopolymers that offer precise sequence control. Six ELP sequences with systematically varied hydrophobicity and charge were designed to investigate how hydrophobicity and charge influence dilute solution phase behavior in 0-40 mol % ethanol and 0-200 mM sodium chloride. Both hydrophobic and hydrophilic ELPs in this study display four characteristic regimes in their phase diagrams: lower critical solution temperature (LCST)-like transitions at low ethanol concentrations, a one-phase region at low-to-moderate ethanol concentrations, upper critical solution temperature (UCST)-like transitions at intermediate ethanol concentrations, and full miscibility at high ethanol concentrations. Despite an identical overall composition with a previously studied ELP sequence, differences in sequence and molecular weight significantly impact phase behavior in ethanol/water mixtures. These results reveal both sequence dependence in the phase behavior of ELPs and universal cononsolvency behavior in uncharged hydrophobic and hydrophilic ELPs.

Objective: This work aimed to elucidate the molecular mechanisms by which human umbilical cord mesenchymal stem cell (HUMSC)-derived extracellular vesicles (EVs) loaded with microRNA-183-5p (miR-183-5p) mitigate sepsis-induced acute kidney injury (AKI), focusing on the downregulation of thrombospondin-1 (THBS1) and suppression of the TGF-β pathway. Methods: A cecal ligation and puncture (CLP) model was established to induce sepsis-induced AKI in mice, and an in vitro injury model was generated by exposing human renal tubular epithelial cells (HK-2 cells) to lipopolysaccharide (LPS). miR-183-5p expression levels in injured tissues and cells were assessed using RT-qPCR. EVs were isolated from HUMSCs via ultracentrifugation, and miR-183-5p-loaded EVs were prepared using electroporation. These loaded EVs were then administered to mice to assess their impacts on renal function, histopathological alterations, and apoptosis. Bioinformatic prediction identified THBS1 as miR-183-5p's potential target, which was verified through miRNA mimic transfection, dual-luciferase reporter assays, and THBS1 overexpression rescue experiments. Results: miR-183-5p expression was reduced in both the sepsis-induced AKI mouse model and LPS-treated HK-2 cells. Administration of miR-183-5p-loaded EVs effectively reduced serum inflammatory cytokine levels, improved renal function, and reduced apoptosis, thereby alleviating sepsis-induced AKI in mice. miR-183-5p directly targeted and inhibited THBS1 expression, thereby reducing LPS-induced apoptosis in HK-2 cells. Further experiments revealed that THBS1 promoted inflammation and apoptosis through the activation of the TGF-β pathway. Conclusion: HUMSC-derived EVs loaded with miR-183-5p effectively mitigate sepsis-induced AKI by targeting THBS1 and inhibiting the TGF-β pathway, thereby reducing inflammation and apoptosis.

Effective bone regeneration requires not only robust osteoinduction but also precise immunomodulation to orchestrate the complex healing process. In this study, we present a strategy for engineering multifunctional three-dimensional (3D) stem cell spheroids (Sphe-BP-IL4-BMP2) by integrating black phosphorus (BP) nanosheets coloaded with interleukin-4 (IL-4) together with recombinant human bone morphogenetic protein-2 (rhBMP-2). BP nanosheets served as a biodegradable scaffold and a delivery vehicle, enabling sustained release of rhBMP-2 and IL-4 to enhance osteogenic differentiation and to promote anti-inflammatory M2 macrophage polarization, respectively. The resulting spheroids exhibited a well-defined morphology, enhanced cell viability, and uniform BP nanosheet distribution. The in vitro studies demonstrated Sphe-BP-IL4-BMP2 has significantly upregulated osteogenic markers and ALP activity alongside potent immunomodulatory effects on macrophages. Further in vivo implantation into a rat calvarial defect model led to increased angiogenesis and accelerated bone regeneration without adverse effects. The results highlight the therapeutic synergy between osteoinductive and immunomodulatory cues within a 3D spheroid platform, offering a promising avenue for treating critical-sized bone defects.