Biomaterials最新文献

Muscle injury or degeneration in the head and neck region can impair daily swallowing function. Mesenchymal stem cell (MSC) therapy has shown potential for muscle regeneration but faces challenges like poor cell survival and limited engraftment. Click-crosslinked nanogel-based hydrogels have emerged as promising cell delivery systems. This study introduces nanogel-microfiber fragments (NG-MF) as structural spacers within spheroids to enhance cell viability and function. By modifying cholesterol-bearing pullulan with acryloyl groups (CHPA) nanogels, we synthesized NG-MF using freeze-thaw cycles and sonication. NG-MF were then combined with adipose-derived MSCs (ADSCs) to fabricate hybrid spheroids. The NG-MF to ADSC ratio was optimized in hybrid spheroids, resulting in approximately a 5.6-fold increase in cell viability relative to cell-only spheroids. Hybrid spheroids also showed elevated secretion of key repair-associated factors, including interleukin (IL)-6, IL-10, and hepatocyte growth factor. This enhanced secretory function was maintained after the spheroids were refined to a smaller, injection-compatible size of approximately 100 μm for in vivo delivery. In rats with injured swallowing muscles, hybrid spheroid injection enhanced cell engraftment, reduced fibrosis, accelerated myogenin stabilization, and improved swallowing muscle function compared to cell-only spheroids. Cell engraftment rose by 20.8% from in vivo biodistribution analysis, and swallowing amplitude improved by 9.0% from electromyographic data three weeks post-treatment. The addition of NG-MF spacers in spheroids facilitates in situ injection-based delivery of ADSCs, thereby potentially enhancing in vivo swallowing muscle regeneration.

Ferroptosis has been proven as a promising therapeutic approach with immunomodulatory effect; however, intracellular antioxidant system maintains redox balance and diminishes its efficacy. Nuclear factor erythroid 2-related factor 2 (Nrf2) is identified as a central transcription factor for regulating oxidative homeostasis. Herein, we have developed a thermal-controllable genome-editing nanoplatform BF/pHCN. Specifically, a CRISPR/Cas9 plasmid with an upstream HSP70 promoter sequence (HSP70-Cas9-sgNrf2, named pHCN) was constructed. Subsequent Fe(II) and pHCN were co-loaded into organic small-molecule BTP with near infrared II (NIR-II) absorption and coated with DSPE-mPEG₂₀₀₀. The generated BF/pHCN (BTP@Fe/pHCN) could be internalized within osteosarcoma cells. Subsequent NIR-II laser-triggered hyperthermia at 42 °C activated the HSP70 promoter and facilitated the precise inhibition targeting Nrf2 genomic sequences while promoting Fe(II) release, ultimately disrupting oxidative stress states. Moreover, the amplified ferroptosis fully triggered immunogenic cell death, thus reprogramming macrophages, promoting maturation of dendritic cells, and activating cellular antitumoral immunity. Additionally, BF/pHCN exhibited direct bactericidal activity against planktonic bacteria, and effectively eliminated intracellular bacteria through iron metabolic disorders strategy targeting macrophages, thereby initiating adaptive antimicrobial immunity. Overall, our NIR-II thermal-controllable genome-editing nanoplatform BF/pHCN exhibits remarkable antitumoral properties alongside robust antiinfection and immunomodulation, providing feasible strategies toward effective management of osteosarcoma, and preventing postsurgical implant-associated infections.

Liver transplantation is the ultimate therapeutic intervention for patients with end-stage liver diseases. However, hepatic ischemia-reperfusion injury (HIRI) could occur and influence the success of transplantation and postoperative patient survival rates. Although there are several treatments available alleviating the pathology, the efficacy is suboptimal because only the oxidative stress or inflammation involved in HIRI is singly addressed. Given that these two causes are mutually entangled with each other in HIRI, we report a superoxide anion-responsive supramolecular polymer from peptide-H₂S donor conjugates (designated as HMS) to simultaneously address the challenge, thereby augmenting the efficacy. Upon superoxide anion stimulation, HMS controllably releases persulfides/H₂S, which then acts synergistically with methionine residues to exert a potent antioxidant effect, ultimately blocking the initiation of the oxidative stress-inflammation vicious cycle. Besides, the anti-inflammatory sequence SESSE in the conjugate could induce macrophage M2 polarization by modulating the energy metabolism and boost the mitigation of HIRI in vitro. In vivo assessment further shows that HMS could protect mice from HIRI effectively. Owing to its favorable biocompatibility and outstanding therapeutic efficacy, the strategy presented here may inspire new preventive or therapeutic approaches for ischemic diseases.

PROteolysis TArgeting Chimeras (PROTACs) have emerged as a pharmacological tool for selectively degrading disease-associated proteins of interest (POIs). However, PROTACs-mediated protein degradation often lacks precise spatiotemporal control, potentially disrupting protein homeostasis in normal tissues and causing physiological toxicity. To address these challenges, we developed an ultrasound-activated PROTAC prodrug platform (US-PROTAC) that enables spatiotemporally controlled PROTAC activation with non-invasive, in situ fluorescence-guided monitoring. This platform consists of three essential components: a near-infrared fluorescent reporter (methylene blue, MB) for bioimaging feedback, a PROTAC molecule selectively targeting POIs, and a self-immolative linker for ultrasound-triggered activation. The protein degradation activity of US-PROTAC is masked under physiological conditions. However, ultrasonic stimulation generates hydroxyl radicals (•OH) through cavitation dynamics, selectively cleaving urea bonds and restoring MB fluorescence. This process simultaneously triggers a self-immolative reaction that releases active PROTAC. Importantly, MB fluorescence recovery enables real-time visualization of ultrasound-triggered PROTAC release in vitro and in vivo. The combination of ultrasound-mediated activation and fluorescence imaging further enables modulation of therapeutic efficacy by adjusting ultrasound parameters, offering a practical tool for optimizing spatiotemporal control of targeted protein degradation.

Osteoarthritis (OA) progression is driven by persistent oxidative stress and ferroptosis, which erode chondrocyte viability and extracellular matrix integrity. Although mesenchymal stem cell-derived exosomes (MSC-EXO) hold regenerative promise, their native cargo lacks the adaptability to withstand such a hostile microenvironment, limiting therapeutic efficacy. Here, we demonstrated a synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis. Firstly, the reverse-adaptation strategy in which OA-like oxidative stress was harnessed to precondition MSCs, thereby identifying miR-142a-3p as a key therapeutic mediator in tert-butyl hydroperoxide (TBHP)-modified exosomes (T-EXO). Subsequently, we engineered MSC-derived exosomes via miR-142a-3p electroporation (EXO^miR-142a-3p) with unique anti-ferroptosis and antioxidative properties. EXO^miR-142a-3p were markedly enriched with miR-142a-3p, which directly targeted the GSK3β/Nrf2/SLC7A11 axis to suppress ferroptosis and reactive oxygen species (ROS) accumulation. Compared to naive EXO, EXO^miR-142a-3p exhibited superior protection against cartilage matrix degradation and significantly slowed OA progression in a murine model. By integrating these engineered exosomes into a biodegradable, cartilage-targeted, and lubricious microsphere platform, we achieved sustained, site-specific delivery that amplified therapeutic durability and efficacy. This platform robustly mitigated extracellular matrix (ECM) degradation, ferroptosis, and oxidative stress in vitro, and conferred significant cartilage protection in a destabilization of medial meniscus (DMM)-induced OA model via efficient, prolonged intra-articular release. Collectively, this innovative approach not only provides potent cartilage protection in preclinical models but also establishes a paradigm for precision, microenvironment-adaptive regenerative therapies for OA and other degenerative diseases.

Spinal cord injury (SCI) is a debilitating condition that leads to severe motor and sensory dysfunction, largely due to inflammation, neuronal damage, and disrupted neural circuits. In this study, we developed an injectable hydrogel (C/F/Gel) co-loaded with fibroblast growth factor 21 (FGF21) and cannabidiol micelles (CBDm) to enhance SCI repair. The hydrogel, composed of PF127 and α-cyclodextrin (α-CD), provides sustained drug release and improves drug stability at the injury site. Our findings demonstrate that C/F/Gel effectively modulates the inflammatory microenvironment by promoting microglial polarization toward the anti-inflammatory M2 phenotype via cannabinoid receptor 2 (CB2R) activation. Additionally, it regulates the balance between excitatory and inhibitory neurons, and significantly improves motor function in SCI mice. Behavioral assessments, histological analysis, and molecular studies confirmed the superior therapeutic efficacy of C/F/Gel compared to single-agent treatments. These results highlight C/F/Gel as a promising biomaterial-based strategy for SCI repair, offering a synergistic approach that integrates inflammation modulation, neuroprotection, and functional recovery.

Bacterial biofilm eradication and prevention of re-colonization are critical for effective treatment of biofilm-associated infections. Although significant progress has been made in nanovehicle-assisted antimicrobial platforms for biofilm eradication, strategies to address re-colonization remain underdeveloped. In this study, we constructed a versatile antimicrobial delivery platform based on multimodal interaction polyurea nanogels (MIPN). MIPN demonstrated excellent biocompatibility and could effectively load various antimicrobials with high capacity due to the multiple intermolecular interactions between the antimicrobials and nanocarriers, including hydrogen bonding, electrostatic, and hydrophobic interactions. By incorporating self-synthesized quorum sensing inhibitors (QSI) within MIPN, bacteria re-colonization was successfully prevented by blocking the quorum sensing pathway and disrupting surface-associated bacterial motilities. Furthermore, MIPN coloaded with QSI- and antibiotics showed a synergistic effect on biofilm eradication and re-colonization prevention, significantly enhancing the healing of biofilm-associated infections in chronic wounds.

Cuproptosis, a form of copper-dependent programmed cell death, has emerged as a promising therapeutic target for cancer treatment. However, the efficacy of cuproptosis is undermined by metabolic reprogramming, notably the Warburg effect and the overproduction of glutathione stemming from solute carrier family 7 member 11 (SLC7A11) overexpression. Upregulation of the cystine transporter SLC7A11, while providing a survival advantage, also creates a glucose-dependent metabolic vulnerability in cancer cells, offering a new opportunity for cancer treatment through disulfidptosis under glucose deprivation conditions. Herein, we developed copper-based metal-organic framework nanoparticles, CuSS@876-PEG, which exploit metabolic vulnerabilities by consuming glutathione and subsequently releasing copper ions and the glucose transporter inhibitor BAY-876, thereby eliciting cuproptosis and disulfidptosis. This strategy not only enhances cell death but also stimulates immunogenic cell death, activating the antitumor immune response. To summarize, our innovative strategy provides a multifaceted approach to targeting tumors, paving the way for combined cancer therapy.

Junctional hemorrhage is a major prehospital care challenge, causing 67 % of preventable deaths. In addition, the high risk of secondary hemorrhage during transportation remains a challenge for long-term wound protection. Present hemostatic materials can't simultaneously achieve "anti-high-pressure, fast hemostasis and stable blockage". Inspired by coagulation process, positively charged dense cross-linked structure-inherited microgels (PEDM) were prepared. PEDM hybrid blood form quasi-bicontinuous composite structure (Q-Bi CS), utilizing blood realize rapid anti-high-pressure hemostasis and stable protection. PEDM can self-gel within 15 s when contact with blood, mimicking primary hemostasis to form a quick mechanical blockage. Blood cells are concentrated within 50 s, which promotes the Q-Bi CS formed in 120 s. Compared to PEDM-PBS, the compression modulus of PEDM-blood is improved by 5.4 times, achieving robust blockage. Q-Bi CS showed stable dynamic adhesion with strength maintained at 90.1 % after 200 cycles. In the rabbit femoral artery hemorrhage model, PEDM can achieve rapid hemostasis within 61 s and prevent secondary hemorrhage. PEDM even controlled porcine iliac artery hemorrhage within 30 s. In this paper, the self-gelling of PEDM matches with coagulation process, and blood is incorporated as the reinforcing phase into the Q-Bi CS, overcoming the difficulty of junctional hemostasis.

Cell-based therapies offer transformative potential for treating a range of diseases, however, maintaining desirable cell functions under environmental and biochemical stresses remains a major challenge. In the present study, silk ionomer nanoencapsulation using layer-by-layer (LbL) deposition was utilized as a versatile strategy to provide temporary cell protection from these stresses and preserve cell functions for downstream use. Using THP-1 immune cells, tunable encapsulation of the cells with up to 10 bilayers of silk was demonstrated. Characterization by quartz crystal microbalance (QCM-D) and atomic force microscopy (AFM) revealed nonlinear thickness growth (∼800 nm) and peak stiffness of 231 kPa above five bilayers, indicating a transition from rigid initial layer deposition, to softer outer layers. We demonstrate that the silk ionomer coatings preserved cellular functions, including differentiation into M1 and M2 macrophages, the associated cytokine profiles (TNF-α, IL-1β, IL-10, TGF-β), and expression of cell surface markers (CD68, CD206) when compared to the uncoated controls. Notably, these temporary coatings blocked antibody binding to CD14/CD68 receptors and also protected cells from shear stress during extrusion through a 34G needle at 200 μL/min, resulting in greater than a 70 % increase in cell survival compared to the uncoated cells during extrusion. These results establish silk ionomers as a robust biomaterials platform for enhancing the mechanical resilience and immune evasion of cells in advanced applications, such as for 3D bioprinting, adoptive immunotherapy, and regenerative transplantation.