Advanced Materials [IF=27.4]

摘要：The development of prophylactic cancer vaccines typically involves the selection of combinations of tumour-associated antigens, tumour-specific antigens and neoantigens. Here we show that membranes from induced pluripotent stem cells can serve as a tumour-antigen pool, and that a nanoparticle vaccine consisting of self-assembled commercial adjuvants wrapped by such membranes robustly stimulated innate immunity, evaded antigen-specific tolerance and activated B-cell and T-cell responses, which were mediated by epitopes from the abundant number of antigens shared between the membranes of tumour cells and pluripotent stem cells. In mice, the vaccine elicited systemic antitumour memory T-cell and B-cell responses as well as tumour-specific immune responses after a tumour challenge, and inhibited the progression of melanoma, colon cancer, breast cancer and post-operative lung metastases. Harnessing antigens shared by pluripotent stem cell membranes and tumour membranes may facilitate the development of universal cancer vaccines.

摘要：Plant-derived extracellular vesicles(PEVs)have been regarded as a superior source for nanomedicine and drug delivery systems. Nevertheless, their clinical translation is hindered by the lack of clarity and even contradiction in their biomedical applications. Herein, we conducted a comprehensive compositional analysis of four commonly used PEVs to fully understand their functional lipid contents and assess their potential therapeutic applications. The lipidomic analysis revealed the presence of cytotoxic gingerols and shogaols in ginger-derived EVs(GEVs). Subsequent in vitro and in vivo investigations substantiated the remarkable tumor cell inhibitory and tumor growth suppression efficacy of GEVs. The transcriptomic analysis indicated that GEVs regulate the cell cycle and p53 signaling pathways, thereby inducing cancer cell apoptosis. The supplementary proteomic analysis suggested the potential protein markers in PEV research. These findings highlight the value of multi-omics analyses in elucidating the potential therapeutic effects of PEVs and in advancing the development of PEV-based therapies.

摘要：Diabetic osteoporosis, a prevalent chronic complication of diabetes, is marked by reduced bone mass, increased bone fragility, and susceptibility to fractures. A significant cause of this condition is the disruption of osteoblastic homeostasis due to prolonged hyperglycemia, which impedes bone regeneration and remodeling. Despite its prevalence, no effective treatments specifically target diabetic osteoporosis. Recently, small-activating RNA(saRNA)therapy has attracted attention for its targeting capacity, high efficacy, and minimal side effects. However, RNA’s inherent properties, such as structural instability, susceptibility to degradation, and poor penetration, limit its applications. To address these limitations, a gene-activating tetrahedral framework nucleic acid(tFNA)with sirtuin-1(SIRT1)gene activation function is developed, termed Tsa. Tsa exhibits an RNA-protecting effect and can effectively penetrate cell membranes to upregulate SIRT1 gene expression. At the histological level, Tsa treatment alleviates diabetic osteoporosis by increasing bone trabecular density and promoting new bone formation. At the cellular level, it switches macrophage polarization toward the anti-inflammatory M2 phenotype while inhibiting the inflammatory M1 phenotype, creating a favorable bone immune microenvironment for osteoblasts. At the genetic level, Tsa activates SIRT1 expression, which deacetylates Acetyl-p65 to block the NF-κB pathway and restore the osteoimmune environment. Overall, this research demonstrates a nanodrug “Tsa”, capable of activating SIRT1 and modulating the bone immune environment, thereby showcasing its immense potential for diabetic osteoporosis treatment.

摘要：Ferroptosis plays an important role in radiotherapy(RT), and the induction of ferroptosis can effectively sensitize radiotherapy. However, the therapeutic efficiency is always affected by ferroptosis resistance, especially SLC7A11(Solute Carrier Family 7 Member 11)-cystine-cysteine-GSH(glutathione)-GPX4(glutathione peroxidase 4)pathway-mediated resistance. In this study, tumor-microenvironment self-activated high-Z element-containing nanoferroptosis inducers, PEGylated Fe–Bi–SS metal–organic frameworks(FBSP MOFs), were developed to sensitize RT. Unexpectedly, ferroptosis-resistant SLC7A11 would be self-adaptively upregulated, leading to self-responsive ferroptosis resistance. Since the conversion from SLC7A11-transported cystine to cysteine is highly glucose-dependent, glucose oxidase(GOx)was incorporated in the MOFs, causing the depletion of NADPH(nicotinamide adenine dinucleotide phosphate)to terminate the conversion from cystine to cysteine, relieving the self-adaptive ferroptosis resistance. Excitingly, the accumulation of cystine would synergistically lead to disulfide stress and trigger disulfidptosis, making a new contribution to enhance therapeutic efficiency. Moreover, the hydrogen peroxide produced during glucose oxidation could also cascade-react with the Fenton reaction, therefore enhancing ferropotosis. Both in vitro and in vivo results suggested that therapeutic efficiency of ferroptosis-mediated radiosensitization could be enhanced benefiting from synergistic disulfidptosis induction, indicating that disulfidptosis might be an efficient strategy to relieve ferroptosis resistance and enhance RT efficiency.

Science [IF=44.7]

摘要：Orofacial muscles are particularly prone to refractory fibrosis after injury, leading to a negative effect on the patient's quality of life and limited therapeutic options. Gaining insights into innate inflammatory response-fibrogenesis homeostasis can aid in the development of new therapeutic strategies for muscle fibrosis. In this study, the crucial role of macrophages is identified in the regulation of orofacial muscle fibrogenesis after injury. Hypothesizing that orchestrating macrophage polarization and functions will be beneficial for fibrosis treatment, nanomaterials are engineered with polyethylenimine functionalization to regulate the macrophage phenotype by capturing negatively charged cell-free nucleic acids(cfNAs). This cationic nanomaterial reduces macrophage-related inflammation in vitr and demonstrates excellent efficacy in preventing orofacial muscle fibrosis in vivo. Single-cell RNA sequencing reveals that the cationic nanomaterial reduces the proportion of profibrotic Gal3⁺ macrophages through the cfNA-mediated TLR7/9-NF-κB signaling pathway, resulting in a shift in profibrotic fibro-adipogenic progenitors(FAPs) from the matrix-producing Fabp4⁺ subcluster to the matrix-degrading Igf1⁺ subcluster. The study highlights a strategy to target innate inflammatory response-fibrogenesis homeostasis and suggests that cationic nanomaterials can be exploited for treating refractory fibrosis.

摘要：In liver transplantation, donor livers are typically stored in a preservation solution at 4°C for up to 12 hours. However, this short preservation duration can lead to various issues, such as suboptimal donor-recipient matching and limited opportunities for organ sharing. Previous studies have developed a long-term preservation method called supercooling liver preservation(SLP) to address these issues. However, in this study using a rat model, we observed that long-term SLP led to more severe liver damage compared with clinically prevalent traditional static cold storage(SCS) for durations less than 8 hours. To understand the potential mechanism of SLP-induced liver injury, we conducted an integrative metabolomic, transcriptomic, and proteomic analysis. We identified the PDE3B-cAMP-autophagy pathway as a key determinant of SLP-induced liver injury. Specifically, we found that PDE3B was elevated during SLP, which promoted a reduction of cAMP metabolites, triggering an AMPK-dependent autophagy process that led to liver injury in rats. We found that blocking the reduction in cAMP using the PDE3B inhibitor cilostamide inhibited autophagy and substantially ameliorated liver injury during 48-hour SLP in rat livers. Furthermore, we validated the effectiveness of cilostamide treatment in preventing liver injury in pig and human liver 48-hour SLP models. In summary, our results reveal that metabolic reprogramming involving the PDE3B-cAMP-autophagy axis is the key determinant of liver injury in long-term SLP and provide an early therapeutic strategy to prevent liver injury in this setting.

摘要：The coronavirus disease 2019(COVID-19)pandemic has driven major advances in virus research. The role of glycans in viral infection has been revealed, with research demonstrating that terminal sialic acids are key receptors during viral attachment and infection into host cells. However, there is an urgent demand for universal tools to study the mechanism of sialic acids in viral infections, as well as to develop therapeutic agents against epidemic viruses through the downregulation of terminal sialic acid residues on glycans acting as a glyco-virus checkpoint to accelerate virus clearance. In this study, we developed a robust sialic acids blockade tool termed local and noninvasive glyco-virus checkpoint nanoblockades(LONG NBs), which blocked cell surface sialic acids by endogenously and continuously inhibiting the de novo sialic acids biosynthesis pathway. Furthermore, LONG NBs could accurately characterize the sialic acid-dependent profiles of multiple virus variants and protected the host against partial SARS-CoV-2, rotavirus, and influenza A virus infections after local and noninvasive administration. Our results suggest that LONG NBs represent a promising tool to facilitate in-depth research on the mechanism of viral infection, and serve as a broad-spectrum protectant against existing and emerging viral variants via glyco-virus checkpoint blockade.

摘要：Recent research has highlighted the pivotal role of lipoxygenases in modulating ferroptosis and immune responses by catalyzing the generation of lipid peroxides. However, the limitations associated with protein enzymes, such as poor stability, low bioavailability, and high production costs, have motivated researchers to explore biomimetic materials with lipoxygenase-like activity. Here, we report the discovery of lipoxygenase-like two-dimensional (2D) MoS₂ nanosheets capable of catalyzing lipid peroxidation and inducing ferroptosis. The resulting catalytic products were successfully identified using mass spectrometry and a luminescent substrate. Unlike native lipoxygenases, MoS₂ nanosheets exhibited exceptional catalytic activity at extreme pH, high temperature, high ionic strength, and organic solvent conditions. Structure–activity relationship analysis indicates that sulfur atomic vacancy sites on MoS₂ nanosheets are responsible for their catalytic activity. Furthermore, the lipoxygenase-like activity of MoS₂ nanosheets was demonstrated within mammalian cells and animal tissues, inducing distinctive ferroptotic cell death. In summary, this research introduces an alternative to lipoxygenase to regulate lipid peroxidation in cells, offering a promising avenue for ferroptosis induction.