Biomaterials research最新文献

Osteoporosis (OP) is the most common bone metabolic disorder worldwide, markedly compromising patients' quality of life and imposing a substantial healthcare burden. However, current clinical treatments for OP are not able to provide satisfactory therapeutic outcomes, particularly in the presence of complex inflammatory conditions. The integration of noninvasive physical therapy and bionanotechnology has shown great promise in modulating cellular functions and optimizing the bone microenvironment. In this study, we demonstrated that electromagnetized gold nanoparticles (AuNPs) exhibited excellent biocompatibility at the cellular, vascular, and major organ levels. These electromagnetized AuNPs significantly enhanced the biological behaviors of osteoblasts, including proliferation, migration, colony formation, and osteogenic differentiation. Remarkably, RNA sequencing analysis revealed that electromagnetized AuNPs significantly activated the mitochondrial oxidative phosphorylation pathway while suppressing the interleukin-17 pro-inflammatory signaling pathway. Additionally, electromagnetized AuNPs stabilized mitochondrial membrane potential and boosted adenosine triphosphate (ATP) production while reducing cell apoptosis and oxidative stress, thereby promoting osteogenic differentiation under inflammatory conditions. Furthermore, in a mouse model of inflammation-induced OP, the electromagnetized AuNPs effectively restored bone mass and improved trabecular architecture. Collectively, our findings provide a proof-of-concept that electromagnetized AuNPs enhance osteogenesis by promoting osteogenic differentiation and optimizing the bone microenvironment, highlighting their potential as a promising therapeutic strategy for OP.

Copper plays multifunctional roles in both physical processes and cancer development. Since copper is an excellent candidate for Fenton-like reactions and the inducer of cuproptosis, copper-based antitumor drugs have attracted many researchers in recent years. However, there are still some barriers to their clinical application, such as leakage to normal tissues, excess of glutathione (GSH), and lack of H₂O₂ in the tumor microenvironment, indicating that copper alone is not enough for cancer therapy. Herein, we constructed a DNA-based nanodrug loaded with Cu²⁺ and glucose oxidase (GOx) for synergistic cancer therapy, namely, glucose oxidase-copper-DNA hybrid nanoflower (GCD). AS1411 aptamer, coded in the long single-stranded DNA sequence, provided GCD with tumor-targeting ability, enhancing its bio-safety. The addition of GOx not only provided adequate H₂O₂ but also helped deplete GSH. Besides, as it oxidated glucose to gluconic acid, the main energy source of tumor cells was cut off. The in vitro and in vivo antitumor ability of GCD was verified. We also examined immune cell death induction and the immune regulation role of GCD and found that the combination of anti-programmed death-1 antibody further enhanced its antitumor effect. These results contribute to the further study and application of copper-based drug development.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by aberrant T cell activity and excessive autoantibody production. Follicular helper T cells (Tfh) play a pivotal role in promoting B cell-mediated autoantibody generation, contributing to SLE progression. Although mesenchymal stem cell-derived exosomes (MSC-Exos) exhibit immunomodulatory properties, their effects on Tfh in SLE and the underlying mechanisms remain unclear. To address this, we first analyzed sorted Tfh from an imiquimod-induced lupus murine model (IMQ-SLE) and found that MSC-Exos effectively suppressed Tfh function. Consistently, Tfh polarization assays demonstrated that MSC-Exos modulate Tfh differentiation in vitro. Subsequently, we evaluated the therapeutic potential of intravenous MSC-Exos administration and confirmed that MSC-Exos markedly inhibited Tfh expansion and function in vivo. Further RNA sequencing followed by validation experiments identified that MSC-Exos restore calcium homeostasis in Tfh. Mechanically, MSC-Exos down-regulate stromal interaction molecule 1 (Stim1) and Orai1 expression, inhibiting nuclear factor of activated T cells (NFAT) and nuclear factor κB (NF-κB) activation. In parallel, MSC-Exos mitigate calcium overload-induced mitochondrial damage by suppressing mitochondrial calcium uniporter (MCU) expression. Finally, we observed that MSC-Exos also promote the differentiation of follicular regulatory T cells (Tfr) both in vivo and in vitro. These findings suggest that MSC-Exos ameliorate SLE by correcting cellular calcium dysregulation and mitochondrial damage in Tfh while simultaneously restoring the Tfh/Tfr imbalance, highlighting their potential as a therapeutic strategy for SLE.

The interplay between nuclear architecture and extracellular matrix stiffness orchestrates cell fate decisions, yet the molecular mechanisms remain poorly defined. Here, we investigate the role of Lamin A (LMNA), a nuclear structural protein whose expression correlates with tissue stiffness, in regulating cellular differentiation and fate decision. Using myoblasts and fibroblasts as models, it was observed that cells with low LMNA expression showed that higher cell deformation elevated expression of neurological genes and exhibited potential for differentiation into a neural-like fate. CUT&Tag sequencing of LMNA-knockdown cells revealed a reduction in the size of Lamin B1-associated domains, with enhanced Lamin B1 binding at muscle-related genes (Myf5 and Myf6) and diminished binding at the neural gene Nes, suggesting that changes in gene expression are associated with alterations in chromatin structure. Further analysis identified the dissolution of H3K9me2/3-labeled heterochromatin regions and their redistribution in the nucleoplasm following LMNA inhibition. Soft substrates (0.2 kPa) amplify the neural differentiation capacity in LMNA-knockout cells. Additionally, retinoic acid was shown to enhance the expression of neurologically related genes by suppressing LMNA expression. These findings reveal a novel substrate stiffness-induced mechanism by which Lamin A regulates cell fate transitions and provide a new approach for neural cell generation.

The use of injectable hydrogels represents a viable approach for enhancing neural repair and promoting functional restoration after spinal cord trauma. Nevertheless, the current performance of these materials is not yet optimal and further optimization is necessary. Engineering a cell-free hydrogel delivery system with sustained anti-inflammatory capacity is of great relevance for advancing therapeutic strategies in spinal cord injury (SCI). Here, we fabricated a biomimetic hydrogel incorporating spermidine to modulate the post-injury immune microenvironment. The material was constructed by photocrosslinking aldehyde-modified methacrylated hyaluronic acid (AHAMA) through dynamic Schiff base chemistry, enabling controlled and prolonged spermidine release. This hydrogel demonstrated expedited gelation kinetics coupled with stable and exceptional mechanical properties. In addition, the cell-free AHAMA hydrogels have substantially enhanced the cellular-matrix interactions and facilitated neuronal integration. Furthermore, the spermidine-loaded hydrogel exerted potent immunomodulatory effects by suppressing M1 macrophage (classically activated macrophage) polarization through activation of STAT1 (signal transducer and activator of transcription 1) signaling axis. In vivo assessments demonstrated enhanced neuroregeneration and axonal elongation at the lesion site, which translated into marked improvements in locomotor function in the murine SCI model. Collectively, the combination of sustained spermidine release with a bioinspired, cell-free AHAMA hydrogel scaffold offers an effective therapeutic approach to modulate inflammation and enhance tissue repair in the injured spinal cord environment.

Atherosclerosis is the leading cause of global cardiovascular morbidity and mortality associated with inflammatory and immunological mechanisms. Immunotherapy has demonstrated promising efficacy in the management of atherosclerosis. Nevertheless, certain immunotherapeutic approaches are associated with limitations, including suboptimal efficacy and non-negligible adverse effects. Upon the pivotal role of macrophage phenotypes in atherosclerosis progression, naringenin-loaded manganese-doped mesoporous silica nanoparticles (MMSN@NAR) were designed and synthesized to reprogram M1 macrophages toward the M2 phenotype, thereby offering a potential therapeutic strategy for atherosclerosis treatment. High loading capacity of naringenin was achieved in MMSN carriers, with superior biocompatibility profiles compared to naringenin dissolved in dimethyl sulfoxide, while maintaining pH-dependent release behavior as demonstrated by dialysis assays. MMSN@NAR is preferentially phagocytosed by M1 macrophages, attenuates inflammatory responses, protects against oxidative stress, and promotes M2 polarization via the AMP-activated protein kinase (AMPK) pathway in vitro. In the ApoE^-/- mouse unilateral carotid artery ligation model of atherosclerosis, MMSN@NAR demonstrated marked accumulation in plaques and excellent biocompatibility. Compared to using naringenin or MMSN alone, it could further reduce plaque area by approximately 40% or 60% by inducing macrophage phenotype transformation, which was confirmed by section staining and immunofluorescence. Collectively, this study highlights enhanced macrophage M2 polarization inhibiting atherosclerosis by MMSN@NAR as a promising nanoplatform, offering a novel therapeutic approach based on anti-inflammatory immune regulation.

Sepsis-induced liver injury (SILI) is a serious complication of septicemia and contributes to high rates of patient death. SILI is characterized by excessive hepatic reactive oxygen species (ROS) generation, leading to inflammatory response activation and the release of inflammatory mediators that yield liver damage. Efforts to design drugs that can mitigate oxidative stress and inflammatory factor production are thus vital to protecting patients against SILI. Nevertheless, effective pharmacological interventions for SILI therapy are currently absent. Here, natural superoxide dismutase (SOD)-mimetic carbon dots (G-CDs), derived from the traditional medicine plant Glycyrrhiza, with robust ROS-scavenging activity were designed and synthesized as a novel treatment for SILI. These G-CDs possess abundant surface hydroxyl and carbonyl groups such that they can effectively mediate SOD-like enzyme activity exceeding 13,340 U/mg to alleviate ROS overproduction and associated inflammation. In a murine model of lipopolysaccharide-induced SILI, these G-CDs effectively reduced hepatic inflammation, oxidative injury, and tissue damage. From a mechanistic perspective, these G-CDs were found to preserve liver integrity through the activation of Keap1/Nrf2-mediated antioxidant signaling and the inhibition of NF-κB-dependent inflammation, thereby reducing the levels of hepatic inflammation and oxidative stress. In summary, these results highlight the promise of G-CDs as therapeutic candidates capable of treating SILI by mitigating oxidative stress-associated liver injury.

Mesoporous metal nanomaterials (MMNs) have gained interest in biomedicine for their unique properties, but their potential is limited by the predominance of spherical shapes and the neglect of morphological effects on biological activity, which hinders the reasonable evaluation of morphology-dependent enzyme-like activities and biological behaviors and its further biomedical applications. It is therefore imperative to find an effective and facile method to design and prepare MMNs with novel, well-defined morphologies. Herein, we fabricated 3 mesoporous platinum nanoenzymes including sphere, rod, and bipyramid topologies [Au@mesoPt sphere, Au@mesoPt rod, and Au@mesoPt bipyramid nanoparticles (NPs), respectively] via a facile atomic layer deposition method using gold NPs (Au NPs) as the templated cores and Pluronic F127 as a structure-directing agent. The obtained Au@mesoPt NPs could enhance cellular uptake efficiency and prolong blood elimination half-lives, which helped more cancer cell spheroid permeation and accumulation at the disease sites post-injection. Au@mesoPt NPs could obviously alleviate atherosclerosis through reactive oxide species (ROS) scavenge due to its catalase-like activity and inhibition of pro-inflammatory cytokine release. Due to the role of metal nanoenzymes containing high-order-number (Z) elements as radiosensitizers, Au@mesoPt NPs have a distinct radiosensitizing on pancreatic cancer treatment. Among the shapes, Au@mesoPt bipyramids showed the best therapeutic efficacy in treating atherosclerosis and pancreatic cancer, likely due to their high aspect ratio, irregular surface, and anisotropy, which favor blood flow and cellular uptake. The tunable synthesis of shape-defined MMNs bodes well for other areas of application, including biosensors, surface-enhanced Raman scattering, surface plasmon resonance, hydrogen storage, catalysis, and electrotherapy.

Cancer is a devastating disease, and its pathogenesis is highly associated with malnutrition and poor lifestyle. Chemotherapy continuously causes inadequate therapeutic efficacy and induces off-target toxicities. Hence, targeted co-administration of chemotherapy and dietary supplement producing anticancer effect at low doses with minimized toxicities would be a promising strategy for cancer treatment. In this study, we constructed chondroitin sulfate (CS) and methotrexate (MTX) carried serum albumin nanocages (C/M@Alb NCs) by albumin nanoreactor strategy. During fabrication, we achieved the precipitation of MTX and CS inside the albumin nanocore under mild reaction condition to prepare C/M@Alb NCs. The enhanced anticancer efficacy of C/M@Alb NCs was comprehensively assessed by in vitro and in vivo experiments. Biodistribution, pharmacokinetic profile, and in vivo therapeutic efficacy of C/M@Alb NCs were investigated in human colorectal adenocarcinoma (HT-29), murine breast cancer (E0071), and patient-derived (PDX) lung cancer models. The as-prepared C/M@Alb NCs facilitated higher MTX and CS encapsulation, exhibiting small particle size, improved colloidal stability, dual stimuli (pH/GSH)-responsive drug release profile, an enhanced cellular uptake, cooperative synergistic cytotoxicity, extended blood residence time, improved lymph node and tumor targeting, and in vivo therapeutic efficacy against various cancers such as human colorectal adenocarcinoma, murine breast cancer, and patient-derived (PDX) lung cancer. Altogether, C/M@Alb NCs exhibited enhanced cellular uptake, extended blood residence time, and favorable tumor accumulation and lymph node extravasation, finally leading to the potent antitumor efficacy against various cancers. This nanoplatform offers a new strategy for designing lymph node- and cancer-targeted albumin-based nanomedicine for clinical applications.

The utilization of mesenchymal stem cells (MSCs) serves as an encouraging strategy for treating liver fibrosis. However, precise mechanisms are not completely understood. Recently, small extracellular vesicles (sEVs) have emerged as major paracrine effectors mediating the anti-fibrotic effects of MSCs. This study seeks to examine the healing properties of MSCs-sEVs on liver fibrosis and decipher the associated signaling pathways. Herein, MSCs substantially ameliorated carbon tetrachloride (CCL4)-induced liver inflammation and fibrosis in mice, with this effect predominantly attributed to their derived sEVs. Both in vivo and in vitro experiments verified that MSCs-sEVs skewed the phenotype of liver macrophages into an anti-fibrotic phenotype. Mass spectrometry analysis showed that ubiquitin-specific peptidase 10 (USP10) was significantly enriched in MSCs-sEVs, which was critical for protection against liver fibrosis. USP10 stabilizes Krüppel-like factor 4 (KLF4) via deubiquitination, participating in the modulation of macrophage phenotypes. Mechanistically, KLF4 reprograms macrophages to enhance their anti-inflammatory and repairing functions by modulating NF-κB/STAT6 signaling and regulating the transcription of MMP12. Finally, the exogenous incorporation of USP10 into MSCs-sEVs via genetic engineering further potentiated their antifibrotic effects. These findings deepen the knowledge regarding the cellular pathways through which MSCs ameliorate liver fibrosis, offering a theoretical basis for sEV-based therapeutic strategies.