Biomaterials research最新文献

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.

Three-dimensional (3D) bioprinting is a promising field in tissue engineering, and the mechanical properties and biocompatibility of bioinks are essential factors. This study introduces a biocompatible, thermo-responsive poly(organophosphazene)-based bioink with excellent mechanical properties that provides effective drug release. First, we synthesized the Tyr-PPZ polymer, which contained an isoleucine ethyl ester, amino-methoxy poly(ethylene glycol), and tyramine. The Tyr-PPZ polymer was dissolved in phosphate-buffered saline to prepare TP bioink. The presence of hydrophobic components facilitated the homogeneous diffusion of caffeic acid into the bioink and conferred antioxidant properties. The PC bioink, prepared by incorporating caffeic acid into TP bioink, not only exhibited stable antioxidant properties but also showed excellent extrudability and printability due to its shear-thinning and recovery properties, which enabled the fabrication of various 3D scaffolds. Printed 3D scaffolds maintained high mechanical properties at body temperature (37 °C), which ensured scaffold stability for 30 d without additional cross-linking. In addition, to enhance diabetic wound healing through antioxidant properties and fibroblast delivery, PCC bioink was formulated by loading fibroblasts into PC bioink. Three-dimensional scaffolds fabricated using PCC bioink exhibited high cell viability for 7 d and promoted tissue regeneration in diabetic mice. In addition, PCC bioink provided antioxidant effects and accelerated wound closure, thick granulation tissue formation, and angiogenesis. This technology is promising as a next-generation bioink platform for diabetic wound treatment through a high-resolution 3D bioprinting scaffold that effectively delivers antioxidants and fibroblasts.

This research examines the impact of exosomes derived from mesenchymal stem cells that have been pretreated with ginsenoside Rh2 (Rh2-pre Exo) in the context of collagen-induced arthritis (CIA). Rheumatoid arthritis (RA) is a persistent inflammatory condition marked by joint pain and swelling, which, in advanced stages, may result in joint damage and reduced functionality. We found that Rh2-pro Exo regulates the Toll-like receptor 4 (TLR4)/Myd88/nuclear factor κB (NF-κB) signaling pathway by modulating the m6A methylation levels of C-C motif chemokine receptor like 2 (CCRL2). The interaction between CCRL2 and TLR4 is a key factor influencing the activity of this signaling pathway. Our results indicate that this regulatory mechanism enhances the anti-inflammatory phenotype of macrophages, promoting a shift from pro-inflammatory to anti-inflammatory responses. Furthermore, treatment with Rh2-pre Exo substantially alleviated clinical symptoms and reduced joint damage in CIA models. These findings provide new insights into the therapeutic potential of Rh2-pre Exo in the treatment of RA, emphasizing the importance of m6A methylation in regulating immune responses. This study suggests that targeting the m6A methylation pathway of CCRL2 could offer a promising strategy for developing effective therapies for RA, ultimately improving patient outcomes and quality of life.

Artesunate (ART), an antimalarial drug, has been identified as a ferroptotic agent, inducing the generation of reactive oxygen species (ROS) and lipid peroxidation, which, in turn, activate endoplasmic reticulum (ER) stress responses and promote mitochondrial-dependent apoptosis. In our previous studies, we demonstrated that ART enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through crosstalk between the ER stress-mediated signal pathway and the Bid-Bax mitochondrial apoptotic cascade. To further explore the mechanisms underlying ferroptotic-apoptotic crosstalk and evaluate the potential of intra-arterial drug-eluting microspheres for targeted tumor therapy, we developed artesunate-eluting microspheres (ART-EMs) and investigated the tumoricidal efficacy of ART-EMs combined with TRAIL. Our findings reveal that the combined ART-EMs with TRAIL (AT) treatment synergistically enhances cancer cell death. Specifically, we observed increased apoptosis in HCT116 and BxPC-3 cell lines, accompanied by notable morphological changes and enhanced cytotoxicity. Importantly, our results demonstrate that the pro-apoptotic proteins Bid and Bax play essential roles in driving synergistic apoptosis during AT treatment. Furthermore, the contrasting apoptotic responses between AT treatment and the chemotherapeutic agent mitomycin C's dependence on p53-Bak-associated pathways underscore the differential activation of intrinsic apoptosis pathways across cancer cell lines. This study provides deeper insight into the roles of Bak and Bax in orchestrating apoptosis, offering potential strategies for more effective cancer treatments.