Biomaterials research最新文献

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection has been associated with severe cardiovascular complications. However, the role of epitranscriptional modulation involved in SARS-CoV-2-infected myocarditis is still unclear. Ten-eleven translocation 2 (TET2), a methylcytosine dioxygenase, plays key roles in DNA demethylation during viral infection and host-virus interactions. Using human-induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a platform, our data revealed the epitranscriptomic role of TET2 during SARS-CoV-2 infection. First, our RNA sequencing analysis revealed the alterations of the messenger-RNA-expression profiles of epitranscriptomic regulators, including TET2, in hiPSC-CMs during SARS-CoV-2 infection. Second, silencing TET2 markedly reduced both the messenger RNA and protein levels of the viral nucleocapsid (N) protein, leading to attenuated viral replication in infected hiPSC-CMs. Furthermore, RNA dot-blotting analysis revealed that TET2 knockdown suppressed the levels of 5-hydroxymethylcytosine in SARS-CoV-2-infected hiPSC-CMs. To further explore the therapeutic relevance of TET2 inhibition in suppressing SARS-CoV-2 infection, we screened and compared 3 structurally distinct TET2 enzymatic inhibitors: Bobcat339, TETi76, and TFMB-2HG. Among these, Bobcat339 demonstrated the most potent antiviral effect, markedly suppressing SARS-CoV-2 replication and N-protein expression. Molecular docking analysis revealed that Bobcat339 exhibited a high binding affinity for multiple viral targets, including nsp16, RdRp, and N protein, indicating a multitarget mechanism of action. In addition, our data demonstrated that treatment with Bobcat339 can suppress SARS-CoV-2 infectious activity and N-protein expression in infected hiPSC-CMs. Together, our findings highlight the regulatory role of TET2 in SARS-CoV-2 infection and identify Bobcat339 as a promising therapeutic compound. Understanding TET2-driven epitranscriptomics and the functions of TET-targeting inhibitors may provide a novel strategy for mitigating viral infection in SARS-CoV-2-induced cardiomyopathy.

Keloids are pathological scars characterized by excessive proliferation of fibroblasts and abnormal extracellular matrix (ECM) accumulation, largely mediated by transforming growth factor-β1 (TGF-β1). Current therapeutic approaches often fail due to high recurrence and limited selectivity. Here, we investigate the potential of human hair-derived keratin (HK) as a biomaterial with selective anti-fibrotic activity. Using multiple in vitro models including 2D monolayers, 3D spheroids, fibroblast-keratinocyte coculture, and collagen gel contraction, we evaluated the effects of 0.5% HK on keloid fibroblasts (KFs) and normal dermal fibroblasts (DFs), with and without TGF-β1 stimulation. HK selectively inhibited KF proliferation, viability, and migration while sparing DF. In 3D models, HK significantly reduced KF-mediated spheroid expansion and collagen matrix contraction, even under profibrotic stimulation. Mechanistically, HK activated intrinsic apoptotic signaling, up-regulating pro-apoptotic proteins (Bax, caspase-3, CYCS) and down-regulating Bcl-2 and XIAP. Transcriptomic profiling revealed that HK down-regulated pathways associated with ECM-receptor interaction, focal adhesion, and aminoacyl-tRNA biosynthesis in KF, suggesting a dual modulation of fibrotic remodeling and mitochondrial function. These findings demonstrate that HK exerts selective anti-fibrotic and pro-apoptotic effects on pathological fibroblasts, with minimal impact on normal cells. By modulating both ECM organization and cell survival pathways, keratin demonstrates strong potential as a therapeutic biomaterial for targeted keloid treatment.

Photodynamic therapy (PDT) is a promising cancer treatment modality due to its minimally invasive nature and spatiotemporal selectivity. However, its effectiveness is substantially hindered by tumor hypoxia. In this study, bismuth vanadate/molybdenum disulfide@hyaluronic acid (BiVO₄/MoS₂@HA, BM@HA) nanoparticles were engineered to overcome the challenges of tumor hypoxia in PDT. The formation of p-n heterojunctions between MoS₂ and BiVO₄ facilitated electron transfer from MoS₂ to BiVO₄, imparting BM@HA with photothermal properties in the near-infrared (NIR) region and achieving an improved photothermal efficiency of 51.9%. After 808-nm laser irradiation, the electron transfers and the energy generated by photothermal effects enhanced the separation of electron-hole pairs in BM@HA, leading to the production of reactive oxygen species and the hydrolysis of oxygen. Animal experiments revealed the strong tumor-targeting capability of BM@HA, as shown by tumor photothermal imaging and in vivo small-animal imaging. Following 808-nm laser irradiation, it enabled precise tumor phototherapy by combining PDT with photothermal therapy. Furthermore, proteomic analysis revealed that BM@HA + NIR may induce necroptosis of tumor cells by activating peptidylprolyl isomerase D-related pathways. In summary, the BM@HA photosensitizer facilitated NIR photocatalytic oxygen hydrolysis, overcoming the hypoxia limitation in PDT. When combined with photothermal therapy, it displayed improved antitumor efficacy, offering a new strategy for the treatment of oral squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) have successfully transformed clinical oncology against various cancers. However, their widespread utility is limited by low response rates and severe adverse events; thus, a safe and effective approach is required to address these issues. Here, we report the nanoengineering of an anti-programmed cell death-1 antibody (aPD-1) to boost the therapeutic effects following direct local administration into tumors. Specifically, we prepared an aPD-1 nanoformulation using biocompatible mesoporous polydopamine nanoparticles (MPNs) that allow facile and efficient surface functionalization of aPD-1 via latent reactivity to proteins. The nanoformulation increased the antagonistic activity of aPD-1 against PD-1 receptors by enhancing their avidity interactions, effectively blocking PD-1 immune checkpoint signaling in T cells to restore their activation and effector function. The nanoformulation administered via local intratumoral injection enhanced tumor retention of aPD-1 and elicited strong antitumor efficacy against local tumors and long-term tumor recurrence. Our results indicate that robust immune checkpoint signaling blockade in the local tumors using nano-ICI treatment can effectively orchestrate antitumor immunity for local and systemic cancer treatment. Overall, this study underscores the potential of a biomaterial-based nanoengineering approach for improving the efficacy and safety of antibody-based ICI therapy with localized tumor treatment.

Human umbilical cord mesenchymal stem cell extracellular vesicles (hucMSC-EVs) exhibit remarkable potential for alleviating type 2 diabetes mellitus (T2DM). However, the role of hucMSC-EVs in T2DM, particularly concerning oxidative damage to pancreatic β cells, remains underexplored. This study utilized a high-fat diet and streptozotocin (STZ)-induced T2DM mouse model and an STZ-induced INS-1 cell damage model to investigate the effects and mechanisms of hucMSC-EVs. In the T2DM mouse model, hucMSC-EVs effectively lowered blood glucose levels, improved lipid metabolism disorders, and preserved liver function. Moreover, hucMSC-EVs enhanced insulin sensitivity and mitigated oxidative damage. Histological analysis confirmed that hucMSC-EVs marked alleviated liver, kidney, and pancreatic tissue damage. In vitro studies demonstrate that hucMSC-EVs enhance glucose absorption and glycogen synthesis in an insulin-resistant HepG2 model and stimulated insulin secretion in INS-1 cells under high-glucose conditions. In the STZ-induced INS-1 oxidative damage model, hucMSC-EVs protect against oxidative damage by increasing antioxidant enzyme activities, reducing reactive oxygen species production, and decreasing cell apoptosis. The effects were partially mediated by the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT and signal transducer and activator of transcription (STAT) signaling pathways, as well as the up-regulation of key antioxidant proteins such as Nrf2, SOD1, and Bcl2. Further research revealed that miR-191-5p, which is enriched in hucMSC-EVs, targets DAPK1 to activate the PI3K/AKT pathway, thereby contributing to the protective effects against oxidative damage. These findings highlight the critical role and underlying mechanisms of hucMSC-EVs in ameliorating metabolic dysfunction in T2DM, particularly the protective effects against oxidative damage, thus providing a novel strategy for the treatment of T2DM.

Guided bone regeneration (GBR) has become a standard modality for treating localized jawbone defects in the clinic. For optimal bone regeneration, the GBR membrane must be biodegradable and exhibit superior mechanical properties. Zinc, a biodegradable metal, has demonstrated marked potential for use in GBR membranes. To address the insufficient mechanical properties of pure zinc membranes, a Zn-0.3Fe-0.05Mg membrane with enhanced mechanical performance was developed in this study. The Young's modulus, hardness, ultimate tensile strength, and elongation at break of the Zn-0.3Fe-0.05Mg membrane were 47.94 ± 7.38 GPa, 0.58 ± 0.08 GPa, 294.07 ± 7.16 MPa, and 20.67% ± 0.15%, respectively, all of which were superior to those of the pure zinc membrane. Moreover, at a concentration of less than 25%, the membrane extract was not cytotoxic, while in the concentration range of 10% to 25% (zinc concentration of 37.33 ± 3.50 to 93.33 ± 8.75 μM), the membrane extract induced the M2 polarization of Raw264.7 cells. Then, at membrane extract concentrations of 10% to 25%, the osteogenic differentiation of MC3T3-E1 cells and vascularization of human umbilical vein endothelial cells (HUVECs) were promoted in the Raw264.7-MC3T3-E1 and Raw264.7-HUVEC coculture systems. Furthermore, scanning electron microscopy, microcomputed tomography, and histological analyses revealed that the Zn-0.3Fe-0.05Mg membrane promoted M2 macrophage polarization and angiogenesis in vivo, thereby facilitating early bone formation after 2 to 4 weeks. These findings suggest that the Zn-0.3Fe-0.05Mg membrane can degrade and release Zn²⁺ to regulate M2 macrophage polarization and promote early vascularized bone regeneration, showing the potential of Zn-0.3Fe-0.05Mg membranes as ideal GBR membranes.

Replacing damaged salivary glands with in vitro-generated artificial glands offers a fundamental solution for salivary gland dysfunction. However, this approach remains challenging due to the gland's complex structure and cellular heterogeneity. Since natural organogenesis of salivary glands successfully orchestrates these complex processes, replicating the developmental niche in vitro is considered a promising solution. However, it consists of complex, branched structures formed by multiple factors; thus, recapitulation of these factors in vitro using a single type of biomaterial is difficult to achieve. Therefore, this study aims to design a scaffold capable of spontaneously mimicking salivary gland's developmental niche. Herein, we demonstrate that catechol-incorporated polyacrylonitrile (PAN-C) nanofiber scaffold spontaneously transforms into biomimetic structures by adsorbing embryonic mesenchyme-derived extracellular matrix (ECM) and growth factors. Accumulated adsorption of ECM and growth factors on PAN-C nanofibers promoted the proliferation, morphogenesis, and functional differentiation of embryonic salivary gland (eSG) organoids in vitro. Transcriptome analysis revealed that the PAN-C nanofiber scaffold effectively reduced mechanical stress-induced gene expression while promoting proliferation and differentiation of salivary gland epithelial cells. In eSG organoids cultured on PAN-C nanofiber scaffolds, the proportion of functional acinar cells expressing apically localized aquaporin-5 was substantially higher than those cultured on polycarbonate membranes, a conventional culture material. Therefore, PAN-C nanofiber scaffolds provide an effective and economical method for generating functional eSG organoids in vitro.

PIWI-interacting RNAs (piRNAs) are known to be involved in germline development, but their potential mechanisms in carcinogenesis remain elusive. Herein, we investigated the roles of hsa_piR_016975, a novel piRNA, in hepatocellular carcinoma (HCC) progression and its therapeutic effects on drug resistance to sorafenib. The results disclosed that hsa_piR_016975 was highly expressed in HCC and promoted HCC growth, metastasis, epithelial mesenchymal transition (EMT) formation, and sorafenib resistance. Mechanistic research uncovered that hsa_piR_016975 could target inhibition of the expression of serpin family B member 5 (SERPINB5; also known as Maspin) while up-regulating glutathione peroxidase 4 (GPX4) expression, thereby attenuating the ferroptosis and resulting in HCC progression and drug resistance. Furthermore, a novel delivery system was constructed, which was encapsulated with sorafenib and hsa_piR_016975 inhibitor in the nanoparticles of polylactic-co-glycolic acid and subsequently coated with the HCC cell membrane (namely, in-016975/Sora@PLGA-CM). The nanocomposites could effectively reverse HCC progression and sorafenib resistance by inducing hsa_piR_016975/Maspin/gpx4 axis-mediated ferroptosis in both subcutaneous xenograft model and orthotopic transplantation model. Overall, this study illuminates the critical role and molecular mechanisms of hsa_piR_016975 in hepatocarcinogenesis and provides a promising piRNA-oriented nanodelivery strategy for overcoming sorafenib resistance in HCC.

Metal-organic frameworks (MOFs) have immense potential for biomedical applications. This paper reports the development of multifunctional zirconium-based metal-organic framework (ZrMOF) nanohybrids, featuring a photodynamic porphyrin-framed zirconium cluster with photothermal polydopamine (PD) coating. The PD-coated ZrMOF (PD/ZrMOF) nanohybrids exhibit enhanced colloidal stability and biocompatibility. The PD/ZrMOF nanohybrids in the present study exhibited a unique combination of functionalities, including photodynamic therapy (PDT), photothermal therapy (PTT), and the delivery of anticancer agents. Furthermore, hydrazone-modified doxorubicin (DOX-hyd) was encapsulated within the PD/ZrMOF nanohybrids, enabling a pH-responsive release mechanism that responds to acidic conditions within the tumor microenvironment. This study examined how MOFs influence autophagy, which is essential for maintaining cellular homeostasis in various human diseases, resulting in autophagy activation by MOF treatment. Additional research into the possible mechanisms of autophagy by MOF showed that the up-regulation of Beclin-1 and ATG7, independent of the mTOR pathway, contributes to autophagy induction. Furthermore, the DOX-hyd-encapsulated PD/ZrMOF nanohybrids (DOX-hyd-PD/ZrMOF) exhibited remarkable cancer suppression ability in vitro and in vivo, owing to their tri-mode therapeutic capabilities comprising PDT, PTT, and chemotherapy. This versatile "three-in-one" nanoplatform enables efficient cancer imaging and offers a powerful strategy for multi-mode combination treatments.

Cancer remains a leading cause of mortality globally. Combating cancer while safeguarding organs (CCSO) has emerged as a specialized field that employs a multifaceted approach to cancer management. Postsurgery solid tumors face issues such as recurrence and organ dysfunction due to residual cancer, resection, inflammation, and infections. Adjuvant and preventive treatments may also impair organ function, adding to treatment challenges. This review delineates the multifaceted landscape of multidimensional nanomaterials, spanning from 0-dimensional nanoparticles to 3-dimensional scaffolds, and their collaborative roles in concurrent cancer management and organ protection. We underscore the importance of nanomaterial synthesis, functionalization, and responsive release mechanisms in the tumor and organ microenvironments. A comprehensive analysis of nanomaterial applications in integrated cancer management, including melanoma, osteosarcoma, breast cancer, liver cancer, pancreatic cancer, and gastric cancer, is presented, highlighting their potential to overcome therapeutic challenges. The discourse also addresses the obstacles and future directions for nanomaterials for CCSO, offering valuable insights for advancing cancer management and organ protection. This review aims to enhance the comprehension and progress of nanomaterials for CCSO, fostering the development of more effective cancer management modalities.