Periprosthetic osteolysis and aseptic loosening are the leading causes of total joint arthroplasty failure. Wear debris triggers chronic sterile inflammation, driving excessive osteoclast activation and insufficient osteoblastic bone formation. Drug-target Mendelian randomization showed that genetically predicted higher systemic expression of glucagon-like peptide-1 receptor (GLP-1R) is causally associated with a reduced risk of clinical revision arthroplasty. Histological analysis confirmed GLP-1R expression within osteolytic bone tissues. Whether local activation of GLP-1R could counter particle-induced osteolysis, however, remained untested. To address this, we evaluated the therapeutic potential of the GLP-1R agonist, Exendin-4, across animal models and in vitro assays. In a murine model of ultra-high-molecular-weight polyethylene (UHMWPE)-induced calvarial osteolysis, local Exendin-4 administration significantly mitigated bone resorption, suppressed osteoclastogenesis, and stimulated periprosthetic bone formation. Mechanistically, Exendin-4 shifted macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, reducing osteolytic cytokines such as IL-6 and TNF-α; In vitro, it also acted directly on osteoclast precursors to suppress RANKL-driven osteoclastogenesis and rescued the osteogenic differentiation of bone marrow mesenchymal stem cells. These findings demonstrate that targeting GLP-1R signaling effectively restores the uncoupled bone homeostatic axis, offering a promising translational strategy for treating periprosthetic osteolysis. STATEMENT OF SIGNIFICANCE: Periprosthetic osteolysis (PPO) caused by wear debris is a major cause of joint replacement failure. While traditional treatments focus only on slowing down bone loss, strategies that can both stop bone destruction and promote bone healing are critically needed. In this study, we combined human genetic evidence with animal models to show that targeting the local GLP-1 receptor via Exendin-4 effectively treats PPO. Locally delivering Exendin-4 successfully switches pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype and directly rescues the multi-stage bone formation process of stem cells under wear-particle stress, without causing systemic toxicity. This study provides a practical, biosafe strategy for reusing clinical metabolic drugs to balance bone remodeling and extend implant survival.
The incorporation of calcium phosphates to additive manufacturing, particularly digital light processing (DLP), has gained increasing attention for the fabrication of bone tissue engineering scaffolds. DLP enables the production of patient-specific constructs with complex architectures and high spatial resolution. In this study, we develop photo-crosslinkable resin formulations based on poly(ethylene glycol) diacrylate (PEGDA) loaded with reactive α-tricalcium phosphate (α-TCP) particles for DLP printing. Using a liquid crystal display-based DLP (LCD-DLP) system, composite scaffolds were directly printed. High-resolution gyroid architectures containing 50 wt% α-TCP and a designed open porosity of 50% were successfully fabricated. The printed scaffolds exhibited controllable multiscale porosity and underwent an in situ hydrolysis reaction after printing, reaching more than 92% conversion of α-TCP to biomimetic calcium deficient hydroxyapatite (CDHA) composed of high-aspect-ratio nanocrystals. This phase transformation generated an entangled nanocrystalline network that increased the specific surface area and induced structural hardening, resulting in an interpenetrating polymer-ceramic composite architecture. As a consequence, the compressive strength of the scaffolds nearly doubled relative to the as-printed state while maintaining appreciable flexibility. Compared to conventional sintered calcium phosphate scaffolds, the reactive composite scaffolds exhibited markedly improved toughness and flexibility, with almost two-fold increase in strain energy density. Furthermore, the reactive scaffolds showed good cytocompatibility in vitro. These results demonstrate that combining DLP with reactive calcium phosphate-based resins enables the fabrication of mechanically resilient and biologically relevant bone scaffolds through a single-step printing process followed by low temperature in situ hardening. STATEMENT OF SIGNIFICANCE: Traditional 3D-printed bone scaffolds often rely on high-temperature sintering, producing brittle structures prone to failure. We introduce a reactive resin, combining poly(ethylene glycol) diacrylate and α-tricalcium phosphate, designed for Digital Light Processing (DLP). DLP offers significantly higher spatial resolution and architectural complexity than conventional micro-extrusion methods, allowing for more precise patient-specific geometries. Post-printing, an in situ reaction transforms the material into a toughened, interpenetrating polymer-ceramic network. This unique architecture doubles compressive strength and significantly enhances flexibility compared to traditional ceramics. By replacing fragile, sintered components with this resilient, nanocrystalline structure, our approach provides a robust, single-step pathway for creating mechanically durable, cytocompatible scaffolds essential for effective bone tissue engineering.
Tendon injuries rank among the most prevalent musculoskeletal disorders. Their clinical treatment remains challenging due to the inherently poor self-healing capacity and highly ordered hierarchical architecture of native tendon tissues. In recent years, electroactive fiber-based biomaterials have attracted growing attention in the field of tendon regeneration, attributed to their unique capability to mimic the fibrous microstructure of natural tissues while providing therapeutic electrical stimulation throughout tissue repair. In this review, recent advances in electroactive fibrous scaffolds for tendon repair are summarized, with particular focus on their biological functions and regenerative potential. First, the review introduces the bioelectrical microenvironment of native tendon tissues and explains its importance in tissue remodeling and healing. Then, the fundamental design strategies of biomimetic fibrous scaffolds are discussed, including fiber architecture, mechanical characteristics, and commonly used fabrication techniques. Different categories of electroactive material systems and electrically assisted repair approaches are then presented, including conductive scaffolds for wired electrical stimulation, piezoelectric scaffolds that generate electrical signals through physiological-motion-driven stimulation, and externally activated systems such as ultrasound (US) or magnetic fields (MF). Recent progress in intelligent electrotherapeutic platforms that integrate sensing, stimulation, and adaptive regulation into one integrated system is also outlined. Finally, current challenges associated with the clinical translation of electroactive fibrous scaffolds are analyzed, and prospective research directions in this field are proposed. STATEMENT OF SIGNIFICANCE: Electroactive fibrous scaffolds provide a unique opportunity to reconstruct both the anisotropic architecture and the bioelectrical microenvironment of injured tendon. However, fibrous scaffold design, electroactive materials, and electrical stimulation have largely been reviewed as separate topics. This review integrates these areas from a fiber-centered perspective and establishes a structure-property-stimulation-regeneration framework linking fiber alignment, hierarchical assembly, and functional-component distribution with mechanical behavior, electrical transduction, and tendon-regenerative responses. Conductive, motion-driven piezoelectric, remotely activated, and monitoring-enabled systems are critically compared within this framework. By defining how electroactive functions can be engineered through fibrous architecture, this review provides design principles for advancing passive tendon scaffolds toward programmable regenerative biointerfaces.
This study examines the important role of neuro-tumoral crosstalk in oral squamous cell carcinoma (OSCC) progression and therapy. We identified that dorsal root ganglia (DRG)-secreted substance P (SP) activates a pro-metastatic Tacr1-Tlr7 neuroinflammatory axis. To therapeutically disrupt this axis, a multifunctional photosensitive hydrogel patch (PDA/Rop-Ce6@DA-HA) was engineered. This patch co-delivers the local anesthetic ropivacaine (Rop) to block SP release from neurons and the photosensitizer chlorin e6 (Ce6) for combined photothermal (PTT) and photodynamic therapy (PDT). Under near-infrared irradiation, the patch enabled controlled drug release and synergistic PTT/PDT effects. In orthotopic and subcutaneous OSCC models, this combinatorial strategy markedly reduced SP levels, inhibited the Tacr1-Tlr7 axis and downstream PI3K/Akt signaling, increased tumor cell apoptosis, and produced stronger antitumor effects. The results support a biomaterial-based strategy that combines local neuromodulation with phototherapy for OSCC treatment. STATEMENT OF SIGNIFICANCE: This study develops a photosensitive PDA/Rop-Ce6@DA-HA hydrogel patch that integrates photothermal therapy, photodynamic therapy, and local neural modulation for oral squamous cell carcinoma. By blocking DRG-derived substance P release and suppressing the SP-Tacr1-Tlr7 axis, the biomaterial targets neuro-tumoral crosstalk while enabling localized light-triggered tumor ablation. The work links biomaterial design with a defined neuroinflammatory mechanism and provides a combined strategy for improving oral cancer treatment.
Zirconium-based metal-organic framework (MOF-808) materials were selected as drug delivery carriers, with 5-fluorouracil (5-Flu) as the model drug. MOF-808@5-Flu drug-loaded carriers were designed and prepared at different ratios. The drug release behavior of the MOF-808@5-Flu nanocomposite was investigated under different pH conditions (7.4/6.5/5.0). The results showed that when the mass ratio of MOF-808 to 5-Flu was 1:0.25, the material released 55.56% of the drug within 50 h at pH 5.0, compared with 47.85% and 48.00% at pH 7.4 and 6.5, respectively. The drug release behavior was well fitted by the Higuchi model the Higuchi model. Cell and animal experiments demonstrated that MOF-808@5-Flu exhibited good biocompatibility and significantly inhibited the growth of Hepa1-6 cells, indicating its potential as a targeted nanocarrier to enhance therapeutic efficacy. Studies indicate that MOF-808@5-Flu induces cancer cell death through the apoptotic pathway. The catalytic activity of Zr4+ acted synergistically with the pharmacological effects of 5-Flu, generated a large amount of reactive oxygen species (ROS), significantly reducing tumor cell viability. Theoretical calculations indicated that MOF-808@5-Flu exhibits synergistic effects through multiple interactions, including π-π stacking, electrostatic attraction, and hydrophobic interactions. This results further highlights the advantages of MOF-808@5-Flu as a drug delivery platform. In summary, MOF-808@5-Flu shows great potential as a targeted nanocarrier for anticancer drug delivery. STATEMENT OF SIGNIFICANCE: Developed MOF-808@5-Flu nanocarriers with strong potential for targeted anticancer drug delivery. Achieved pH-responsive 5-Flu release, with the highest release rate of 55.56% at pH 5.0 within 50 h. Confirmed that the drug release profile follows the Higuchi model. Demonstrated good biocompatibility and effective inhibition of Hepa1-6 tumor cell growth. Revealed a "carrier-drug" synergistic mechanism driven by Zr4+ catalysis and multiple intermolecular interactions.
Successful bone repair requires coordinated regulation of osteogenesis, osteoclast activity, and angiogenesis, yet most bone graft materials address only one or two of these processes. Here, 3D-printed β-tricalcium phosphate scaffolds doped with zinc oxide (ZnO-TCP) and loaded with quercetin (Que) are developed to provide a multifunctional platform for regenerating critical-size defects. ZnO doping enhances densification and mechanical strength, while Zn²⁺ and Que together regulate bone remodeling by suppressing osteoclast activity and promoting osteogenic and angiogenic signaling. In vitro, the combined ZnO-TCP-Que scaffolds significantly reduce Tartrate-Resistant Acid Phosphatase (TRAP) activity, upregulate osteogenic and angiogenic genes, and maintain cytocompatibility. In a rat distal femur model, ZnO-TCP-Que scaffolds increase bone formation by ∼1.5-fold and enhance vascularization by ∼1.8-fold compared to TCP controls. These findings show that co-delivery of Zn²⁺ and Que creates a microenvironment that promotes bone formation, limits resorption, and supports vascular ingrowth. This approach provides a multifunctional ceramic scaffold that can coordinate bone formation, resorption, and vascularization in complex bone defects. STATEMENT OF SIGNIFICANCE: Repairing large bone defects requires coordinated regulation of bone formation, vascularization, and resorption. Most existing biomaterials address only one or two of these processes. Here, we develop a 3D-printed tricalcium phosphate scaffold doped with zinc and loaded with quercetin to simultaneously target these pathways. Zinc improves mechanical strength and supports osteogenic activity, while quercetin provides controlled release and modulates cellular responses. The scaffold reduces osteoclast activity while promoting osteoblast function and endothelial cell behavior. In a rat model, it increased new bone formation by ∼1.5-fold and vascularization by ∼1.8-fold. This work presents a multifunctional approach for designing biomaterials that better support coordinated bone regeneration.
Meniscus repair is often limited by poor intrinsic healing, an adverse oxidative-inflammatory microenvironment, and insufficient mechanical continuity across the tear interface. Here, we engineered a solvent-free injectable polyurethane adhesive (PUA) loaded with connective tissue growth factor (PUA@CTGF) for meniscus tear repair that combines rapid wet interfacial stabilization, compliant defect filling, and prolonged CTGF release. The adhesive showed rapid in situ curing, high apparent initial wet lap-shear strength, and stable short-cycle compressive behavior in a 100-cycle loading-unloading test. In vitro, PUA@CTGF reduced oxidative stress-associated mitochondrial injury, modulated macrophage-associated inflammatory markers toward a more repair-supportive profile, promoted meniscal cell migration, and enhanced fibrochondrogenic matrix synthesis when combined with cyclic tensile stimulation. In a rabbit outer-vascular-zone meniscus tear model, PUA@CTGF improved repair-region continuity, matrix deposition, and tensile properties and attenuated early joint degenerative changes relative to untreated, suture, fibrin, and PUA controls, although native meniscal tensile properties were not fully restored during the 12-week observation period. Transcriptomic profiling identified mechanotransduction-related signatures, while inhibitor-supported in vitro analyses showed that GsMTx4 attenuated dynamic-loading-induced Ca2+ and YAP responses, supporting a GsMTx4-sensitive mechanotransduction response. These findings support PUA@CTGF as a bioactive polyurethane adhesive platform for wet, mechanically active meniscal repair interfaces. STATEMENT OF SIGNIFICANCE: Meniscus tears are difficult to heal because the injured interface is wet, mechanically active, and biologically hostile. This study introduces a solvent-free injectable polyurethane adhesive that rapidly stabilizes wet meniscal tears while providing localized delivery of connective tissue growth factor. By combining catechol-assisted wet adhesion, compliant defect filling, short-cycle energy dissipation, reactive oxygen species buffering, and prolonged CTGF release, the adhesive provides interfacial stabilization and microenvironmental regulation. In vitro and rabbit studies showed enhanced cell migration and matrix-associated responses, improved repair-region continuity and tensile properties, and attenuation of early joint degenerative changes. This work advances biomaterial design by integrating wet interfacial stabilization with localized biochemical delivery for the repair of mechanically active, load-bearing soft-tissue interfaces.
Surgery remains the primary treatment for meningiomas, with radiotherapy used for high-grade tumors, residual disease, and recurrences. However, many high-risk meningiomas progress despite resection or radiotherapy, and effective pharmacological therapies remain lacking. Here, we explored a local microneedle-mediated delivery strategy using gelatin methacryloyl hydrogels (Gel-MA) to co-deliver hydroxyapatite nanoparticles (n-HA) and the selective CDK4/6 inhibitor abemaciclib in meningioma cell-line models. n-HA and abemaciclib were associated with reduced proliferation, increased apoptosis-related signals, and cell-cycle inhibition in the tested models. Exploratory RNA sequencing suggested that n-HA treatment was associated with transcriptional changes related to cellular stress, calcium homeostasis, apoptosis, endocytosis, and immune-related pathways; these findings should be interpreted as hypothesis-generating rather than definitive mechanistic evidence. In an orthotopic xenograft model, local microneedle delivery of n-HA and abemaciclib suppressed tumor progression and was associated with treatment-related histological changes. Overall, this study provides proof-of-concept evidence that a biodegradable microneedle platform may enable local combination therapy for residual, recurrent, or incompletely resectable meningiomas. STATEMENT OF SIGNIFICANCE: Hydroxyapatite nanoparticles (n-HA), a bone-like material, suppress meningioma cell growth while stimulating anti-tumor immune responses, suggesting a therapeutic role beyond structural biomaterials. We further show that n-HA synergizes with abemaciclib to enhance tumor inhibition and immunity. To deliver this combination precisely to the tumor site, we develop GelMA microneedle patches that enable localized and controlled release, reducing reliance on systemic dosing. In animal models, microneedles loaded with n-HA and abemaciclib produce marked anti-tumor effects. Finally, incorporating β-cyclodextrin improves abemaciclib bioavailability, strengthening local therapy. Together, this work introduces an immunoactive biomaterial-drug microneedle strategy with potential for safer, more effective meningioma treatment.
Obesity represents a global health crisis characterized by chronic adipose tissue (AT) inflammation (metaflammation) driven by pro-inflammatory M1 macrophage (MΦ) polarization, adipocyte hypertrophy, and impaired thermogenic capacity of white adipose tissue (WAT). While interleukin-4 (IL-4) potently induces M2 MΦ polarization, its clinical translation is limited by poor stability, rapid clearance, and off-target effects. Here, we engineered lipid nanoparticles (IL-4/LNP) via simple, robust thin-film hydration and extrusion to enable sustained IL-4 delivery to MΦs in inflamed AT. In vitro, IL-4/LNP achieved >70% encapsulation efficiency, a uniform ∼150 nm size, and superior M1 to M2 MΦ reprogramming compared with free IL-4, as evidenced by CD206 upregulation, reduced CD80/CD40 expression, and attenuated TNF-α/IL-6 secretion in LPS-stimulated MΦ. In adipocyte-mimicking cells (3T3-L1)-MΦ co-cultures representing white and brown adipose tissue (BAT), paracrine signaling from IL-4/LNP-polarized M2 MΦs drove a profound reduction in lipid droplets (LDs) and beiging, with decreased Feret diameter and integrated optical density. Using a high-fat diet-induced obese mouse model, localized inguinal/visceral AT injections blunted weight gain by ∼10%, induced multilocular beige-like adipocytes across depots, upregulated thermogenic genes (Ucp1 and Pgc1α), downregulated inflammatory markers (IL-6), and improved hepatic steatosis without systemic toxicity. These findings establish IL-4/LNP as a safe, multifunctional platform that links MΦ immunomodulation and adipose browning in obesity therapy. STATEMENT OF SIGNIFICANCE: This study establishes IL-4-loaded lipid nanoparticles (IL-4/LNPs) as a nanomedicine platform that targets the immunometabolic roots of obesity by reprogramming adipose tissue macrophages and promoting white fat browning. IL-4/LNPs are produced by a simple, scalable thin-film hydration-extrusion method, yielding ∼150 nm particles with ∼73% encapsulation, suitable for local adipose delivery. In vitro, the NPs outperform free IL-4 by enhancing M2 polarization, driving paracrine adipocyte remodeling, and reducing lipid burden in 3T3-L1 co-cultures. In high-fat diet-obese mice, depot-specific IL-4/LNP injections limit weight gain, induce adipocyte beiging, improve hepatic steatosis, and reduce systemic inflammation without detectable toxicity, supporting IL-4/LNPs as a translatable cytokine nanotherapy for metaflammatory obesity.
Hemicellulose, the second-most-abundant biopolymer on Earth, offers a renewable platform for nanomedicine due to its tunable branching chemistry, biocompatibility, and amphiphilic self-assembly. However, clinical translation of hemicellulose-based nanoparticles remains stalled due to the absence of quantitative design rules linking molecular architecture to biological performance. This critical review synthesizes 32 peer-reviewed studies (2010-2025) using a PRISMA-informed data extraction strategy to establish a quantitative structure-property-function framework for hemicellulose-based nanocarriers. Quantitative evaluation reveals that the arabinose-to-xylose ratio dictates nanoparticle morphology, and that degree of substitution (DS) controls self-assembly thermodynamics, following an exponential decay model: CAC = 0.112 × e(-0.82×DS) (R² = 0.94). These relationships enable application-specific design: low branching produces small particles for intravenous targeting. In contrast, high branching favors wound healing. Four case studies illustrating therapeutic paradigms are presented: redox-responsive chemotherapy (5-fold decrease in IC₅₀), photodynamic therapy (10.8-fold decrease in IC₅₀), wound healing (100% closure at day 10), and stimuli-responsive sensing (5600% tensile strain). A translational scoring system (SNFT: Sustainability, Novelty, Feasibility, Translation) is introduced to benchmark clinical readiness. Critical barriers identified include manufacturing scalability, lack of ICH-compliant stability data, and undefined regulatory pathways. Future directions encompass AI-assisted optimization, green synthesis, and integration into implantable devices. By integrating an empirical DS-CAC model with evidence-informed structure-property relationships and a translational roadmap, this critical review provides a framework for the rational engineering of hemicellulose nanotherapeutics. STATEMENT OF SIGNIFICANCE: This review establishes a quantitative structure-property-function framework for the rational engineering of hemicellulose-based nanocarriers in precision biomedicine. Unlike previous descriptive reviews, this work integrates molecular architecture, self-assembly behavior, and biological performance into predictive design guidelines derived from 32 studies published between 2010 and 2025. Key relationships linking arabinose-to-xylose ratio, degree of substitution, and molecular weight to nanoparticle morphology, stability, drug loading, and therapeutic activity are critically analyzed. The review further introduces a translational benchmarking strategy (SNFT framework) to evaluate clinical readiness and manufacturing feasibility. By connecting renewable polysaccharide chemistry with nanomedicine, biomaterials engineering, and AI-assisted optimization, this work provides a roadmap for the development of sustainable and clinically translatable hemicellulose nanotherapeutics.
YAP is a central regulator of cell fate, proliferation, and tissue homeostasis that integrates physical cues from the extracellular matrix (ECM). While stiff environments canonically drive YAP nuclear localization and soft environments promote cytoplasmic sequestration, the logic by which cells integrate mechanical inputs with transient biochemical signals remains poorly defined. Here, we examine how intracellular calcium transients interact with substrate compliance to regulate YAP dynamics and transcriptional outputs across epithelial, myoblast, and fibroblast lineages. Using collagen-coated polyacrylamide hydrogels with tunable mechanics, we show that substrate compliance shapes the kinetics of calcium signaling, calcium-mediated actin remodeling, and YAP nuclear shuttling. We demonstrate that calcium signaling can transiently relax baseline mechanical constraints on YAP activity, triggering nuclear translocation and transcriptional activation even on compliant or non-adhesive substrates where YAP is classically suppressed. We identify substrate compliance as a biophysical regulator that filters the transduction of calcium transients into gene-specific programs. Targets such as CYR61 are induced across all mechanical contexts tested, whereas targets like CTGF and AREG require permissive mechanical conditions. These results suggest a preliminary model in which the mechanical state of the cell tunes the activation barrier for YAP-dependent transcription, enabling context-dependent responses to universal biochemical triggers. We show that destabilizing the F-actin cytoskeleton by promoting depolymerization or sequestering actin monomers results in attenuation of the calcium-mediated YAP activity, while stabilizing F-actin results in amplification YAP activity in response to calcium stimulation. This work reveals a fundamental mechanism by which transient signals integrate with matrix mechanics to produce distinct YAP-dependent outcomes, suggesting new strategies for controlling cell fate in regenerative medicine and engineered tissues. Statement of Significance Although YAP regulation by steady-state mechanical cues is well established, how these cues interact with dynamic biochemical signals such as calcium transients to control gene-specific transcription remains unclear. We show that intracellular calcium transients act as rapid, tunable inputs that promote YAP nuclear localization and target gene expression, even on soft substrates that normally suppress YAP activity. Low-threshold gene targets are activated broadly, whereas high-threshold targets require stiffer environments, positioning substrate mechanics as a biophysical gate that shapes the magnitude, kinetics, and gene specificity of calcium-mediated YAP responses. These findings provide insights into how cells integrate transient calcium signals with steady-state matrix mechanics to regulate proliferation, differentiation, and tissue behavior, and provide a framework for guiding cell fate in engineered tissues, organoids, and regenerative medicine.
Enzyme-powered micro/nanomotors (EMNMs) are a type of self-propelled devices that biologically convert chemical energy into mechanical work through enzyme-catalyzed reactions. Compared to conventional chemically driven counterparts, a significant advantage of these platforms lies in their utilization of endogenous substrates, such as glucose, urea, glycerides, and peptides, to achieve autonomous propulsion. Through the rational design and regulation of functional material components, EMNMs can efficiently perform tasks ranging from active target recognition to autonomous drug loading and controlled release for biomedical applications. Additionally, emerging therapeutic modalities, such as photothermal and starvation therapy integrated with EMNMs, have been extensively investigated for diverse clinical interventions. Up to date, several reviews have outlined general progress in the field, however, a comprehensive synthesis of fabrication strategies and their specific therapeutic applications remain relatively underexplored. To address this gap, this review comprehensively elucidates the design principles and construction strategies of EMNMs through enzyme selection, matrix materials, and morphological structures. Besides, the latest research advances in treating cardiovascular and cerebrovascular diseases, cancer, and urological disorders were also systematically summarized. Through further analyzing current bottlenecks and outlines future directions, this article might aim to providing a cornerstone reference and strategic guidance for future endeavors of EMNMs in related fields. STATEMENT OF SIGNIFICANCE: ∙The core design principles and fabrication methodologies of enzyme-powered micro/nanomotors (EMNMs) are comprehensively elucidated. ∙Systematic structure-activity correlations of EMNMs are established across three pivotal dimensions: enzyme screening, matrix scaffolds and morphological architectures. ∙State-of-the-art advances of EMNM platforms for therapeutic intervention against malignancies, cardiovascular and cerebrovascular pathologies, and urinary tract disorders are thoroughly summarized.
Antibacterial treatment reduces residual bacterial burden in periodontitis, but rapid bacterial killing and lysis can also increase exposure to danger signals such as bacterial DNA (bDNA), which can contribute to cGAS-STING-associated innate immune activation. To address this bactericidal stress-associated inflammation, we constructed a ROS-responsive coordination nanosystem, CPLEA, in which the STING inhibitor C-176 was incorporated during Ag⁺-mediated co-assembly of epicatechin and the sulfur-containing PEG ligand methoxy poly(ethylene glycol)-dihydrolipoic acid (mPEG-DHLA), thereby integrating antibacterial activity with the regulation of post-bactericidal STING-associated inflammation. Without compromising bacterial killing, CPLEA promoted C-176 release under oxidative conditions, and the release profile showed temporal overlap with bacterial killing and bDNA exposure. CPLEA attenuated the inflammatory state of macrophages and relieved the suppression of hPDLSC osteogenic differentiation by macrophage-conditioned medium. Transcriptomic analysis indicated downregulation of cytosolic DNA sensing, NF-κB, IL-17, and osteoclast differentiation programs. In a ligature-induced mouse model of periodontitis, CPLEA attenuated local inflammation and TRAP-positive osteoclast accumulation and reduced alveolar bone loss. Collectively, these findings support bactericidal stress-associated STING signaling as a relevant target during local antibacterial treatment of periodontitis and position CPLEA as a feasible materials-based approach for this purpose. STATEMENT OF SIGNIFICANCE: Periodontitis treatment often requires additional antimicrobial control after mechanical debridement, yet rapid bacterial killing and lysis can increase the exposure of bacteria-derived danger signals and thereby sustain host inflammatory responses. This study develops an oxidation-responsive coordination nanoplatform that integrates antibacterial activity with STING-targeted immunomodulation. By incorporating the STING inhibitor C-176 into an Ag⁺-mediated coordination system, CPLEA enables oxidation-promoted C-176 release within a temporal window overlapping bacterial killing and bacterial DNA exposure. The study further demonstrates that early C-176 intervention more effectively regulates STING-associated inflammatory signaling than delayed intervention. CPLEA attenuated macrophage inflammatory responses, alleviated inflammation-associated suppression of periodontal ligament stem cell osteogenic differentiation, and reduced inflammation, osteoclast accumulation, and alveolar bone loss in experimental periodontitis. These findings highlight the importance of immunomodulator availability during the early phase of bactericidal treatment and provide a biomaterials strategy for integrating residual bacterial control with local host modulation.
Polyacrylic acid-based composites hold substantial promise for intelligent wound dressing applications, owing to their intrinsic hydrophilicity and pH responsiveness. Nevertheless, their clinical translation is hindered by insufficient mechanical properties and excessive adhesion, which are directly induced by high hydrophilicity. Herein, a dual-network Janus hydrogel based on polyacrylic acid (PAA) and sodium alginate (SA), denoted as tannic acid-iron nanoparticles@polyacrylic acid/sodium alginate (TA-Fe NPs@PS Janus), was rationally fabricated. This hydrogel incorporates self-assembled TA-Fe nanoparticles (TA-Fe NPs) with inherent antibacterial activity and magnetic responsiveness. Magnetic enrichment of nanoparticles at the bottom side of the hydrogel not only significantly enhances mechanical toughness via metal-phenolic network (MPN) but also renders the top and bottom layers with distinct intelligent responses to heterogeneous pH microenvironments, thus enabling effective antibiotic-free treatment of infected wounds. TA-Fe NPs@PS Janus integrates high mechanical toughness, sensing performance, and pH responsiveness, enabling monitoring of wound microenvironmental changes through combined responses to pH and ionic variations throughout the recovery process. The physicochemical, mechanical, and rheological properties of the hydrogel were systematically characterized, and in vitro antibacterial assessments were conducted. Results demonstrate that TA-Fe NPs significantly enhance hydrogel toughness: compared with the pristine PAA/SA hydrogel (PS), the composite hydrogel incorporating 0.3% (w/v) TA-Fe NPs exhibits a 1200% increase in tensile toughness (from 0.06 MJ m⁻³ to 0.78 MJ m⁻³). The hydrogel displays high sensitivity and undergoes reversible deformation and intelligent responsive behavior under cyclic pH changes. It not only exhibits high antibacterial efficacy but also demonstrates favorable cytocompatibility. Therefore, this study proposes a smart, stimuli-responsive multifunctional hydrogel dressing for treating chronic wound inflammation and monitoring the healing process, highlighting its potential for clinical applications. STATEMENT OF SIGNIFICANCE: Chronic infected wounds severely threaten human health, yet clinically viable smart wound dressings are lacking. Polyacrylic acid (PAA) hydrogels are attractive for wound management but suffer from poor mechanical toughness and over-adhesion. We fabricate a dual-network Janus hydrogel (TA-Fe NPs@PS Janus) incorporating PAA, sodium alginate and tannic acid-iron nanoparticles. Magnetically concentrated TA-Fe NPs form metal-phenolic networks, boosting toughness by 1044.2% and creating asymmetric pH responsiveness. This cytocompatible hydrogel achieves antibiotic-free antibacterial function and real-time infection monitoring via pH changes. It overcomes key drawbacks of PAA hydrogels, integrates diagnosis and therapy, and offers a translatable strategy for intelligent chronic wound dressings.
Diabetic wounds are highly susceptible to bacterial infection and exhibit impaired healing largely driven by defective neutrophil function. Herein, we developed an immunomodulatory hydrogel hybridized with a diselenide-bridged polymer (HHD) to regulate neutrophil fate for effective wound management. HHD demonstrates stepwise, glucose- and ROS-responsive drug release. The initially released l-arginine and pyridoxamine improve wound microenvironment by promoting angiogenesis and suppressing advanced glycation end products. Upon infection, this remodeled microenvironment enhances the recruitment and antibacterial capacity of neutrophils, enabling diabetic wounds to regain the ability to form early inflammatory zones and promptly clear invasive bacteria. Furthermore, excessive ROS generated from antimicrobial immunity degrades neutrophil-targeted polymers, releasing an NLRP3 inhibitor that suppresses inflammasome overactivation and accelerates neutrophil apoptosis, thereby facilitating macrophage efferocytosis to initiate tissue repair. We tracked HHD-shaped neutrophils and confirmed their efficacy in preventing infection and accelerating wound healing. Collectively, HHD represents a promising treatment platform for neutrophil-dependent diabetic wound care. STATEMENT OF SIGNIFICANCE: Neutrophil dysfunction is a key factor leading to infection and impaired healing of diabetic wounds. Significant challenges remain in achieving comprehensive regulation of neutrophil fate. In this work, we construct an immunomodulatory composite hydrogel to regulate neutrophil fate in diabetic wounds: 1) Improving the wound microenvironment, enhancing neutrophil recruitment, and strengthening its antibacterial activity; 2) Inducing neutrophil apoptosis through the neutrophil-targeting polymer; 3) Facilitating macrophage efferocytosis and phenotypic switching via apoptotic neutrophils, thereby expediting tissue repair.
Selecting effective chemotherapy after immunotherapy remains a major clinical challenge in advanced gastric cancer because patient responses are highly heterogeneous. A major obstacle is the lack of personalized preclinical models that faithfully recapitulate the immune-activated tumor microenvironment (TME) following immunotherapy and enable evaluation of subsequent chemotherapy responses while preserving immune-tumor interactions. Here, we developed an immune-activated co-culture model comprising patient-derived gastric cancer organoids and autologous peripheral blood mononuclear cells (PBMCs). Immune activation was achieved using anti-PD-1-loaded gold nanocages (aPD-1@Au NCs), which integrate near-infrared-triggered photothermal tumor ablation with sustained anti-PD-1-mediated immune modulation. The resulting model recapitulates key features of the post-immunotherapy TME, including enhanced immune-cell infiltration, increased tumor-cell apoptosis, and CD8+ T-cell activation. We then applied this model to evaluate five clinically relevant chemotherapeutic agents, including oxaliplatin, irinotecan, fluorouracil, doxorubicin, and docetaxel, for personalized chemotherapy screening after immunotherapy. Compared with monoculture organoids or non-activated co-cultures, the immune-activated model revealed drug-specific differences in tumor-killing efficacy, immune-mediated chemosensitization, and PBMC toxicity. Among the tested agents, oxaliplatin showed the strongest immune-mediated chemosensitization, whereas docetaxel achieved favorable tumor cell killing with relatively low immunotoxicity. These findings demonstrate that chemotherapy responses after immune activation are highly drug-specific, underscoring the importance of personalized chemotherapy selection following immunotherapy. As a proof-of-concept study, this work establishes an immune-activated patient-derived gastric cancer organoid-PBMC co-culture model that partially recapitulates the post-immunotherapy TME. This model provides a promising framework for developing personalized chemotherapy screening strategies after immunotherapy. STATEMENT OF SIGNIFICANCE: Selecting effective chemotherapy after immunotherapy remains a major challenge in advanced gastric cancer because of substantial interpatient heterogeneity. Progress in personalized treatment is limited by the lack of preclinical models that faithfully recapitulate the post-immunotherapy tumor microenvironment (TME). Here, we developed an immune-activated co-culture model integrating patient-derived gastric cancer organoids with autologous peripheral blood mononuclear cells (PBMCs). Immune activation was achieved using anti-PD-1-loaded gold nanocages (aPD-1@Au NCs), which combine near-infrared-triggered photothermal tumor ablation with sustained aPD-1-mediated immune modulation. This platform preserves patient-specific tumor characteristics while capturing key immune-tumor interactions following immunotherapy. Using this model, we evaluated five clinically relevant chemotherapeutic agents and identified distinct drug-specific differences in tumor-killing efficacy, immune-mediated chemosensitization, and immunotoxicity. As a proof-of-concept study, this work establishes a promising framework for personalized chemotherapy screening after immunotherapy and supports the development of precision treatment strategies for gastric cancer.
Infected skin wounds, particularly those complicated by mature biofilms and metabolically quiescent bacteria, often evade antibiotic monotherapy. Such challenging scenarios call for localized, resistance-resilient strategies that concurrently address pathogen eradication and tissue repair. Herein, we develop a neutrophil extracellular trap (NET)-inspired, ultrasound-responsive fibrous reticular dynamic hydrogel (POPP gel) that integrates bacterial enrichment/capture with sonodynamically amplified killing within an injectable matrix. Mildly cationic porphyrin-grafted poly(pyrimidine) nanoparticles (POPP NPs) are embedded in a dynamically crosslinked network of oxidized hyaluronic acid-phenylboronic acid (OHA-PBA), forming a nanofibrous reticular architecture with high interfacial exposure and adhesion toward LPS-/polysaccharide-rich infectious microenvironments. Upon ultrasound activation, POPP NPs generate reactive oxygen species and synergize with charge-mediated membrane perturbation, enabling broad-spectrum bactericidal activity against Gram-negative and Gram-positive bacteria, including biofilm-embedded and drug-resistant phenotypes. The OHA-PBA network additionally confers shear-thinning injectability, rapid self-healing, wound-conforming coverage, and preserved fibroblast viability and migration. In murine full-thickness infected wounds and rat deep second-degree burn infections, ultrasound-activated POPP gel markedly reduces bacterial burden, accelerates wound closure, and promotes mature tissue reconstruction, characterized by continuous re-epithelialization, organized collagen deposition, and attenuated inflammation. Collectively, this NET-inspired sonodynamic hydrogel provides a modular design framework for localized antibacterial biomaterials aimed at refractory infected wounds. STATEMENT OF SIGNIFICANCE: Infected skin wounds with mature biofilms often resist antibiotics. Drawing inspiration from neutrophil extracellular traps, we develop an injectable sonodynamic hydrogel (POPP gel) that captures bacteria via a nanofibrous cationic network and kills them upon ultrasound activation. The gel also supports fibroblast function and wound healing. In murine infected wound and burn models, it reduces bacterial burden and accelerates tissue repair. This work offers a strategy for localized treatment of refractory infected wounds.
Diabetic chronic wounds remain difficult to treat because hypoxia and insufficient regenerative signaling persist. Although live biotherapeutics offer a promising route to local oxygenation therapy, current methods largely support a single microbial function rather than coordinate microbial oxygenation with regenerative cues. Here, we report a hydrogel living therapeutic material in which a crosslinked hyaluronic acid matrix coordinates a living metabolic module of Synechococcus elongatus with a regenerative module of platelet-rich plasma (PRP). The matrix enables injectability and rapid gelation while supporting microbial metabolic activity and modulating the local retention and release of PRP-derived growth factors. The resulting material sustains oxygen generation and preserves the viability of the living module. Particularly, it reduces intracellular ROS accumulation, promotes fibroblast migration, and enhances endothelial tube formation in vitro. In diabetic wounds, it accelerates wound closure and improves re-epithelialization, collagen remodeling, and angiogenesis. Transcriptomic analysis further reveals coordinated regulation of stimulus-response, immune-related, and cytokine- and chemokine-associated pathways. This work establishes a living therapeutic material framework for integrating microbial oxygenation with regenerative signaling for pathological wound microenvironment remodeling. STATEMENT OF SIGNIFICANCE: Diabetic wounds are difficult to heal because damaged tissues often lack both oxygen and regenerative signals. Current living wound therapies mainly focus on microbial oxygen production, but they rarely coordinate oxygen supply with growth-factor-mediated tissue repair. This study develops an injectable living hydrogel that combines photosynthetic Synechococcus elongatus with platelet-rich plasma in a hyaluronic acid matrix. The material continuously generates oxygen, retains and releases regenerative factors, reduces oxidative stress, and promotes cell migration, angiogenesis, collagen remodeling, and wound closure. By integrating metabolic oxygenation with regenerative signaling, this work provides a strategy for remodeling pathological wound microenvironments and designing living therapeutic materials for chronic tissue repair.
Systemic antibiotics often fail to maintain bactericidal levels at bone and implant-associated infection sites, motivating local antibiotic application. Calcium sulfate (CaSO4) carriers are practical and promising in this application. However, the role of antibiotic-carrier interactions in controlling hydration, microstructure, and drug release remains poorly understood. Using in situ time‑resolved powder X-ray diffraction (XRD), we investigate the hydration of CaSO4 loaded with tobramycin, vancomycin and ceftriaxone. Vancomycin- and ceftriaxone-loaded matrices show hydration kinetics similar to unloaded CaSO4, even though the respective interaction mechanisms are different, whereas tobramycin strongly delays the process, reducing the transformation rate by one order of magnitude. Observed by Scanning Electron Microscopy (SEM), the antibiotics induce very different crystallite sizes and morphologies based on specific dissolution, nucleation and growth behaviors. X-ray computed tomography (XCT) reveals larger pore sizes in tobramycin- and ceftriaxone-containing systems due to limited water transport to the sites of crystal nucleation and growth. Related, non-transformed CaSO4 was partially found. These observations on a macroscale are the result of specific dominant molecular interactions: electrostatic adsorption with hydrogen-bonding in the CaSO4-Tobramycin system, hydrogen bonding for CaSO4-Vancomycin, and calcium complexation for CaSO4-Ceftriaxone. This molecular-level understanding of drug-carrier interactions is necessary to regulate hydration kinetics and microstructure, supporting optimization of local antibiotic delivery systems to improve infection management in orthopaedic and trauma surgery. STATEMENT OF SIGNIFICANCE: Periprosthetic joint infections and fracture-related infections are major complications in orthopaedics. Systemic antibiotic administration may fail to achieve sufficient drug concentration at the infection site and expose patients to systemic toxicity. Local administration overcomes these limitations by delivering high levels of drugs directly to the infection site. CaSO4 is in use as drug carrier but its interaction with specific antibiotics is not fully understood. Our multiscale analytical approach using a combination of dynamic XRD studies and X-ray imaging methods for antibiotic-loading into CaSO4 for tobramycin, vancomycin and ceftriaxone allows us to discover the connection between molecular interactions, macroscopic morphological behavior and loading kinetics. This would enable us to design optimized antibiotic release for local drug administration.
Postoperative scarring and failure of surgically created drainage pathways limit durable glaucoma surgery. We developed a solid plate-type suprachoroidal space (SCS) implant based on hydroxyapatite-coated magnesium (HA-Mg) to provide temporary pathway support, an HA-modified material-tissue interface, and progressive biodegradation. TGF-β2-stimulated human iris pigment epithelial cells were used to assess material-associated effects on migration and fibrotic activation. In a paired-eye normotensive New Zealand White rabbit model, trabeculectomy, sham SCS surgery, titanium, uncoated magnesium, and HA-Mg groups were evaluated for 24 weeks using intraocular pressure (IOP) monitoring, ex vivo SCS angiography, micro-computed tomography, histology, α-smooth muscle actin (α-SMA) immunofluorescence, corneal endothelial assessment, aqueous humor pH, and systemic safety analyses. HA-Mg produced a sustained, stable IOP-lowering profile, whereas both Mg and HA-Mg showed greater net IOP reduction at Week 24 than the other surgically treated groups. HA-Mg showed broader posterior SCS contrast enhancement at Weeks 12 and 24. From Week 4 to Week 24, residual implant volume and surface area decreased by 93.6% and 86.3%, respectively, although residual material remained. Histology and α-SMA analysis were consistent with reduced fibrosis-associated interface remodeling, and Mg and HA-Mg extracts attenuated TGF-β2-induced migration and α-SMA expression. No evident ocular or systemic safety concerns were detected within 24 weeks. HA-Mg therefore supported medium-term preservation of the surgically created SCS outflow pathway while undergoing substantial but incomplete degradation; longer-term studies extending through and beyond complete implant resorption are required to determine whether pathway patency and safety are maintained thereafter. STATEMENT OF SIGNIFICANCE: Glaucoma drainage surgery remains limited by progressive fibrosis, foreign-body responses, and loss of long-term drainage pathway function. Although suprachoroidal space (SCS) approaches provide an alternative aqueous outflow route, maintaining pathway patency while minimizing the burden of permanent implants remains challenging. Here, we developed a biodegradable hydroxyapatite-coated magnesium (HA-Mg) drainage plate designed to provide temporary structural support and gradually degrade during tissue remodeling. The study integrates material characterization, medium-term in vivo evaluation, degradation tracking, fibrosis-associated remodeling assessment, and biosafety analysis in a rabbit model. Our findings support a biomaterial strategy that couples progressive biodegradation with preservation of SCS outflow-associated function, providing a potential framework for next-generation biodegradable implants in glaucoma surgery and other applications requiring temporary tissue-implant interfaces.
