Biomaterials research最新文献

Metabolic reprogramming represents a defining feature of the tumor microenvironment, driving both unchecked proliferation and therapeutic resistance. While conventional single-target metabolic therapies have demonstrated limited efficacy owing to the intrinsic adaptability of tumor cells, recent attention has turned toward natural herbal medicine. Combining broad, multilayered actions with low toxicity, they offer a promising way to modulate tumor metabolism and overcome current therapeutic limits. Herein, this work introduces an Artesunate/Icaritin (ART/ICA) hybrid nanoplatform derived from herbal medicine that employs a multimodal energy depletion strategy for malignant tumor therapy. Coadministration of ICA and ART in a nano-platform produces a mutually reinforcing effect that amplifies inhibition of glucose uptake, strengthens antiangiogenic activity, and intensifies mitochondrial dysfunction, overcoming the limitations of single-pathway interventions. The glutathione-responsive disulfide linkages in the nanomedicine enabled controlled, tumor-selective drug release, enhancing the therapeutic agents' stability and bioavailability. In vitro mechanistic studies supported by RNA sequencing analyses and traditional molecular assays demonstrated that this multimodal approach effectively disrupted cellular energy homeostasis, induced apoptosis, and regulated key metabolic pathways. In vivo evaluations using various tumor models, including hepatocellular carcinoma transgenic mouse models, confirmed significantly enhanced antitumor efficacy, while subcutaneous tumor models showed a tumor inhibition rate exceeding 97%, far surpassing the effects of ART or ICA alone. Furthermore, flow cytometry analyses also confirmed that this strategy modulated the tumor microenvironment by enhancing the infiltration of cytotoxic CD8⁺ T cells and promoting dendritic cell maturation, while the incorporation of a CD47-targeting nanobody further strengthened immune activation and contributed to improved antitumor efficacy.

Although tea consumption has been suggested to affect kidney stone formation, epidemiological evidence remains inconsistent, and the underlying molecular mechanisms are unclear. To assess the association between tea intake and kidney stone risk, we initially conducted a prospective cohort analysis of 481,393 participants from the UK Biobank and a 2-sample Mendelian randomization (MR) analysis. Our findings revealed that heavy tea drinkers (>5 cups/day) had a significantly reduced risk of kidney stones (hazard ratio: 0.79, 95% confidence interval [CI]: 0.72 to 0.86, P < 0.001), and MR analyses confirmed a causal association (inverse variance weighted OR: 0.45, 95% CI: 0.32 to 0.62, P < 0.001). We next explored the effect of epigallocatechin gallate (EGCG), the main bioactive component in tea, on calcium oxalate (CaOx) stone formation. EGCG was found to inhibit the glucose-regulated protein 94/phosphatidylinositol 3-kinase/protein kinase B (GRP94/PI3K/AKT) pathway in human proximal renal tubular epithelial cells, thereby attenuating CaOx crystal-induced oxidative stress and inflammation, and inhibiting crystal-cell adhesion. This finding aligned with the observation that the activated GRP94/PI3K/AKT pathway was positively associated with inflammation-related molecules in renal papillary tissues of CaOx stone formers. Moreover, to enhance renal targeting and therapeutic potential, we synthesized cell membrane-coated EGCG-loaded poly(lactic-co-glycolic acid) (TP-EGCG) nanoparticles, which enhanced renal EGCG delivery and substantially reduced CaOx crystal deposition in a mouse model of CaOx nephrolithiasis. In conclusion, tea consumption protects against kidney stone formation, an effect exerted by EGCG through the GRP94/PI3K/AKT axis, and our novel TP-EGCG nanoparticles show strong potential for targeted prevention and treatment.

Cell-based therapy accompanying articular cartilage regeneration is very promising as one of osteoarthritis (OA) treatments. Here, we report that Tyr-Tyr-Glu (YYE) is effective for articular cartilage regeneration through chondrogenic differentation of mesenchymal stem cells (MSCs). The expression of COL II, COMP, ACAN, and COL X at the mRNA and/or protein levels, together with Alcian Blue and Safranin O staining of 3-dimensionally cultured cell pellets, consistently demonstrated that YYE is an effective chondrogenic promoter of MSCs. Western blot, immunofluorescence, and molecular docking studies suggested that the chondrogenic up-regulation by YYE is mediated through YYE binding to FC-1, which induces translocation of core-binding factor β subunit (CBFβ) from the cytosol into the nucleus, followed by up-regulation of runt-related transcription factor 1 (RUNX1), which is a key factor for chondrogenic differentiation of MSCs. In particular, intra-articular injection of YYE to mouse OA models led to a significant improvements of OA as indicated by lowering OARSI grades and subchondral bone plate thickness, and thus proved its articular cartilage regeneration efficacy.

The aryl hydrocarbon receptor (AhR) is known to bind several exogenous ligands such as natural plant flavonoids, synthetic polycyclic aromatic hydrocarbons, and dioxin-like compounds, but its association with kaempferol (KF) is unknown. Therefore, in this study, AhR was explored as an atopic dermatitis (AD)-regulating target of KF for AD regulation using in silico prediction, and pharmacological prediction and various AD-induced models confirmed that KF exhibited pharmacological activity through AhR regulation. Also, the results of the study showed that KF regulated epidermal differentiation terminal proteins through the AhR pathway in HaCaT cells stimulated with TNF-α/IFN-γ, and the therapeutic effect of KF was also proven in an AD-induced mouse model and a reconstructed human skin model. In this study, AhR was explored as a KF-AD combined treatment target through in silico prediction analysis, and KF was proven to have an AD treatment effect through AhR regulation in vitro and vivo and in the reconstructed human skin model. In particular, KF can be used as a potent inducer of AhR signaling because it protects against AD by enhancing epidermal terminal differentiation through the AhR-mediated pathway in keratinocytes.

Tendinopathy markedly impairs patients' quality of life, yet effective therapies remain limited. Conventional therapeutic strategies have largely overlooked the pivotal role of macrophages (M_φ) and M_φ-mediated immunoregulation in this condition. To address this, we designed a microneedle patch (MP) for the in situ delivery of rosmarinic acid (RosA), aiming to modulate local M_φ phenotype. We evaluated the therapeutic efficacy of this RosA-MP against tendinopathy and investigated the underlying mechanism. Briefly, the RosA-MP was fabricated by incorporating RosA into a microneedle array composed of poly(hydroxyethyl methacrylate-co-3-acrylamidophenyl boronic acid-co-(3-methacrylamidopropyl)trimethylammonium chloride) [poly(HEMA-co-3APBA-co-MAPTAC)], which was covalently linked to a flexible filter paper matrix. Formation of phenylboronic acid ester bonds between the 3APBA moieties and RosA endowed the RosA-MP with enhanced stiffness and skin penetration capability, facilitating sustained RosA release. Furthermore, the MAPTAC moieties provided instant hydrophilic swelling upon skin insertion, accelerating RosA delivery via increased internal osmotic pressure. In vitro and in vivo assays demonstrated that the RosA-MP simultaneously induced in situ M₂ M_φ polarization and scavenged reactive oxygen species. Mechanistic investigation revealed that suppression of the NLRP3 inflammasome contributed to the rationale behind M_φ polarization. Using a collagenase type I-induced rat tendinopathy model, we assessed the therapeutic effects of the RosA-MP. Results confirmed that the RosA-MP effectively treated tendinopathy and exhibited significant advantages over injection therapy.

The liver is essential for a range of metabolic functions, and recent advances in organoid technology have enabled the development of various liver organoids. However, the challenges of replicating the in vivo microenvironment, particularly the extracellular matrix, remain important in liver organoid culture. In this study, we explored the roles of Matrigel, a commonly used extracellular matrix component, in the expansion, polarization, and functional maturation of liver organoids derived from human embryonic stem cells (hESCs) under 3-dimensional suspension conditions. Using multiple assays, we demonstrated that a low concentration of Matrigel supported the efficient expansion of hESC-derived hepatoblast organoids by regulating reactive oxygen species (ROS)-autophagy homeostasis through the inhibition of ROS-AMPK-mTOR-mediated excessive autophagy. Moreover, Matrigel induced the polarization of mature hepatocyte organoids differentiated from hESC-derived expandable hepatoblast organoids via activation of the FAK-ERK-AMPK pathway under 3-dimensional suspension conditions. Our findings underscore the importance of integrin signaling in hepatocyte organoid culture and provide insights for the development of artificial, synthetic, bioactive hydrogels for the large-scale production of hepatocytes for clinical applications.

The effectiveness of chemoimmunotherapy for hepatocellular carcinoma (HCC) is hindered by the weak immunogenicity of chemotherapy-induced immunogenic cell death (ICD). This limitation primarily stems from the insufficient activation of the extracellular adenosine triphosphate (eATP)/P2X7 purinergic receptor (P2X7R)/NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway in dendritic cells (DCs). To address this challenge, we designed ivermectin-MnO₂ nanocomplexes (IMNs) as P2X7R-targeted nanoimmunoamplifiers to enhance the immunogenicity of chemotherapy-induced ICD. The ivermectin component of IMN enhanced liposomal doxorubicin (LD)-induced ICD and increased P2X7R sensitivity to eATP. Additionally, the MnO₂ component of IMN alleviated tumor hypoxia and down-regulated CD39/CD73 expression, thereby preventing eATP degradation. These combined strategies robustly activated the eATP/P2X7R/NLRP3 inflammasome cascade in DCs, eliciting a potent antitumor immune response. In combination with anti-PD-L1 antibody and LD, IMN effectively inhibited tumor growth in orthotopic, subcutaneous, and metastatic HCC mouse models. Our study underscores the crucial role of IMN in amplifying the NLRP3 inflammasome cascade in DCs during ICD, presenting a promising strategy to enhance the efficacy of HCC chemoimmunotherapy.

Cytoxan (CTX), an alkylating chemotherapeutic agent, produces severe testicular toxicity in male patients by generating mitochondrial dysfunction and redox imbalance, resulting in an excess buildup of reactive oxygen species (ROS) that compromises sperm function and fertility. Schisandrin A (SchA), a bioactive compound derived from traditional Chinese medicine Schisandra chinensis, can alleviate this injury by mimicking superoxide dismutase activity to scavenge ROS, but its poor water solubility, inability to penetrate the blood-testis barrier (BTB), and high dosage requirement that cause hepatic and gastrointestinal side effects limit clinical application. This study describes a biomimetic SchA delivery system that leverages TM4 (Sertoli-like) cell membrane-coated protein carriers to enable some degree of targeted delivery to testicular tissue. We named it CAT-SchA@SCM. Briefly, SchA was loaded onto catalase (CAT), and protein nanoparticles were disguised with TM4 cell membranes. Transmission electron microscopy and dynamic light scattering results showed that CAT-SchA@SCM had an average particle size of around 170 nm and was well-dispersed and stable. In vitro and in vivo experiments demonstrated that CAT-SchA@SCM could target Sertoli cells to a limited extent, cross the BTB, considerably scavenge intracellular ROS, inhibit apoptosis, and effectively protect Sertoli cells. In a mouse model of CTX-induced testicular damage, CAT-SchA@SCM dramatically increased sperm motility, testicular weight, and serum testosterone levels. Hematoxylin and eosin staining of major organs demonstrated that CAT-SchA@SCM exhibited favorable biosafety. Additionally, activation of the Nrf2-HO-1 signaling pathway was observed, indicating a potential mechanism underlying the therapeutic effect of CAT-SchA@SCM. Therefore, the findings of this study suggest that this nanocomplex-based treatment may offer a viable approach for addressing CTX-induced testicular injury, with potential clinical applications in the future.

Localized photodynamic therapy (PDT) using a photoactive stent-based catheter involves the direct delivery of reactive oxygen species to the mucosa in esophageal carcinoma; however, the damaged mucosa recovers within 2 to 4 weeks, which considerably limits the clinical application of PDT. Here, we used aluminum(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) as a photosensitizer due to its excellent photochemical durability, low photobleaching, and high quantum yield and investigated whether repeated and periodic PDT via an AlPcS4-embedded stent-based catheter can provide sustained therapeutic efficacy. AlPcS4 was uniformly embedded in silicone membranes via coordination bonding to form a photoactive stent-based catheter. The membrane demonstrated excellent photostability and consistent singlet oxygen generation under near-infrared irradiation, as evidenced by a 67.2% decrease in 9,10-dimethylanthracene fluorescence intensity, even after 90 J cm^-2 irradiation, markedly superior to methylene blue (15.3%) and chlorin e6 (30.9%). Repeated PDT effectively enhanced cell death rates in KYSE-70 cells. In the xenograft model, MRI-based volumetric analysis showed that the tumor volume change in the thrice-PDT group (57.40% ± 9.26%) was significantly lower than those in the control (212.07% ± 38.44%, P < 0.001) and once-PDT groups (130.77% ± 11.25%, P = 0.018), accompanied by apoptotic and necrotic tumor destruction. Repeated PDT at 1-week intervals was technically successful in the porcine esophagus, leading to progressive mucosal injury, luminal narrowing, and apoptosis, while demonstrating sustained therapeutic efficacy. Thus, the minimally invasive repeatable photoactive stent-based catheter may be an effective and safe approach for treating esophageal carcinoma.

Implant-associated infections and foreign body responses remain major challenges in orthopedic and biomedical implant applications. In this study, we report a novel strategy to enhance the antibacterial and biocompatibility properties of magnesium (Mg) alloy implants by applying a biodegradable polycaprolactone (PCL) coating embedded with the host-defense peptide, caerin 1.9 (F3). Three Mg-based specimens, including pure Mg, cold-extruded AZ31, and fully annealed AZ31 (3A), were evaluated following PCL-F3 surface modification. The PCL-F3 coatings demonstrated sustained antibacterial efficacy both in vitro and in vivo, effectively inhibiting methicillin-resistant Staphylococcus aureus (MRSA) for up to 168 h. Among the groups, the 3A-PCL-F3 condition exhibited the most notable performance, with substantially enhanced corrosion resistance, reduced inflammatory responses, and no detectable toxicity to vital organs. In vivo proteomic and metabolomic analyses further revealed that the 3A-PCL-F3 implants promoted the expression of osteogenic markers and activated pathways related to bone mineralization and hemostasis, while avoiding prolonged inflammatory activation at 3 months post-implantation. Notably, histological and cytokine ELISA data confirmed favorable tissue responses, including suppressed IL-1β and IL-10 levels and signs of early immune activation that subsided over time. These findings indicate that PCL-F3-coated Mg alloys, particularly the 3A variant, represent a promising solution for biodegradable implants with dual antibacterial and regenerative functionality. This work lays the foundation for developing degradable Mg alloy biomaterials with enhanced biocompatibility and multifunction for clinical use.