Acta biomaterialia最新文献

Acquired drug resistance in hepatocellular carcinoma (HCC) hinders the clinical therapeutic efficacy of various drugs, but efficient intervention strategies remain scarce. In this study, we reported a coacervate-fusion strategy for inhibiting membraneless organelle stress granules (SGs) via stimuli-induced peptide droplets to reverse sorafenib resistance (SFR) in HCC. SGs are coacervated from translation-stalled mRNAs and RNA-binding proteins, including Ras-GAP SH3 domain-binding proteins (G3BPs), and play a critical role in SFR. The peptide droplets YsF-L^SG are formed by liquid-liquid separation (LLPS) of the sulfatase-responsive peptides YsF and YsF-FGDF containing the G3BP ligand. Characterizations in solution reveal that, upon exposure to arylsulfatase A (ARSA), the peptides YsF and YsF-FGDF undergo LLPS and form agglomerate droplets YsF-L^SG. Investigations of HCC-SFR cells confirm that the YsF-L^SG mixtures are efficiently internalized via clathrin-mediated endocytosis, experience ARSA-responsive hydrolysis in lysosomes and lysosomal escape, and undergo in situ LLPS into droplets. Notably, in situ-formed coacervates YsF-L^SG recruit G3BP2 and target SGs with high tumor permeability. YsF-L^SG coacervates enhance sorafenib-triggered apoptosis by relieving SGs-mediated inhibition of p38-Caspase-3 signaling and thus reversing SFR of HCC cells. Further investigations in HCC cell-derived xenograft (CDX) models confirm that YsF-L^SG peptide coacervates significantly reverse SFR through SGs-targeting and apoptosis-restoring mechanisms. Critically, the combination of the YsF-L^SG peptide coacervates with sorafenib more effectively inhibits HCC-SFR growth and has a stronger antitumor effect accompanied by good biosafety. This study highlights the reversal of HCC-SFR via fusion between internal and external coacervates, offering a new approach for overcoming cancer drug resistance. STATEMENT OF SIGNIFICANCE: Design and application of peptide-based coacervates targeting SGs to overcome drug resistance have rarely been studied. Combining the advantages of in situ formulation of coacervate peptide droplets with SGs-targeting property, we developed YsF-L^SG peptide mixtures that target SGs through in situ sulfatase-responsive LLPS into droplets for reversing the SFR of HCC. YsF-L^SG peptide mixtures present high tumor-permeability and SGs-coalescence potential, undergo CME-involved uptake, experience ARSA sulfatase-responsivity and lysosomal escape, and exhibit potent tumor-killing advantage in HCC-SFR cells and CDX mice model. YsF-L^SG peptide mixtures reverse SFR of HCC through G3BP2-recruited, SGs-targeting and apoptosis-restored mechanisms. This provides a new strategy for developing enzyme-induced LLPS peptide coacervates with drug resistance-reversal capacity.

Gasdermin-mediated pyroptosis has emerged as a promising mechanism in cancer immunotherapy, however, its efficacy is often limited by inefficient activation within the immunosuppressive tumor environment. Herein, we generated an acid-regulating biomimetic liposomal nanovesicle (L-P-Cn-U) for the co-delivery of a photosensitizer prodrug (P-Cn) and a carbonic anhydrase IX (CAIX) inhibitor (U-104). By conducting efficacy screening of various P-Cn prodrugs within the L-P-Cn-U system, we identified L-P-C16-U with identical lipid tail structures, as the optimal candidate due to its strong colloidal stability and reactive oxygen species (ROS) generation efficiency. Our cellular and murine model studies demonstrated that L-P-Cn-U-mediated pyroptosis and immunogenic cell death could convert immunologically cold tumors into hot tumors, thereby enhancing antitumor immunity and concurrently inhibiting tumor cell migration. Mechanistic investigation revealed that the acid-triggered U-104 release from L-P-Cn-U augmented intracellular acidity through CAIX inhibition, which subsequently attenuated PI3K-Akt/mTOR signaling. This result enhances O₂-dependent ROS production and establishes a negative feedback loop for CAIX expression. Collectively, our findings provide a combinatorial strategy that integrates pyroptosis-focused therapy with metabolic regulation, offering a broadly applicable conception to augment cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Herein, we report the rational design and synthesis of a new class of biomimetic liposome by integrating chemically engineered pH-responsive lipids (L-pH) with lipid-like photosensitizer prodrugs (P-Cn). Characterization studies demonstrated an optimal construct (L-P-C16) with identical lipid tails, showing robust stability and reactive oxygen species production. This optimized nanovesicle was subsequently co-loaded with the carbonic anhydrase inhibitor U-104. The resulting L-P-C16-U system was adequately investigated and shown to effectively synergize photodynamic therapy and immunotherapy. Our work provides new insights into liposome engineering strategies for combination tumor therapy.

Accurate assessment of inflammatory bowel disease (IBD) severity is crucial for optimizing treatment decisions and improving prognosis. However, conventional assessment methods are time-consuming and primarily detect anatomical changes at moderate or late stages, limiting timely intervention. Here, we report an HClO‑responsive NIR‑IIb ratiometric nanosensor (CSSS@PMH‑mPEG2000) that combines down‑conversion core-shell nanoparticles with strong NIR‑IIb emission under 808/980 nm excitation and an HClO‑responsive IR780MA dye. By means of dye sensitizing mechanism, the sensor enables dynamic ratiometric quantification of HClO and supports real-time assessment of IBD progression and severity. Comprehensive in vitro and in vivo studies validate CSSS@PMH‑mPEG2000 as a highly sensitive and reliable platform for real-time, quantitative HClO monitoring of IBD in a mouse model. Moreover, ratiometric NIR‑IIb fluorescence imaging effectively captures changes in disease severity, highlighting its potential for assessing treatment efficacy. Together, these findings underscore the translational value of CSSS@PMH‑mPEG2000 for advancing IBD diagnosis and management, while also demonstrating its broader applicability to in situ HClO detection across a range of inflammatory diseases. STATEMENT OF SIGNIFICANCE: Accurate IBD severity assessment is vital for optimizing treatment and prognosis, but conventional methods are time‑consuming and detect mainly mid‑to‑late anatomical changes, delaying intervention. We present an HClO‑responsive NIR‑IIb ratiometric nanosensor (CSSS@PMH‑mPEG2000) combining down‑conversion core-shell nanoparticles with an HClO‑responsive IR780MA dye. Using dye sensitizing mechanism, it enables dynamic ratiometric HClO quantification and real‑time evaluation of IBD progression and severity. In vitro and in vivo studies in a mouse IBD model demonstrate high sensitivity and reliability for real‑time, quantitative HClO monitoring. Ratiometric NIR‑IIb imaging captures disease‑severity changes and supports treatment‑efficacy assessment, underscoring the platform's translational value for IBD management and broader in situ HClO detection in inflammatory diseases.

Recent research has demonstrated that the accumulation of excessive mitochondrial double-stranded RNA (mt-dsRNA) plays a significant role in inflammatory processes. Although interventions targeting mt-dsRNA release have shown efficacy in treating various inflammatory diseases, their therapeutic potential in osteoarthritis (OA) remains unclear. This study elucidates the pivotal role of mt-dsRNA in the pathogenesis of OA. Advancing beyond traditional mt-dsRNA suppression methods, we have developed cerium-integrated dendritic mesoporous silica nanoparticles (Ce@DMSN) designed to deliver the mt-dsRNA release inhibitor IMT1, referred to as Ce@DMSN-IMT1 nanoparticles. These biocompatible nanoparticles possess dual functionalities: a robust mt-dsRNA degradation capability and effective inhibition of dsRNA release, leading to substantial anti-inflammatory effects. Intra-articular administration of Ce@DMSN-IMT1 nanoparticles significantly reduced cartilage degradation and synovitis in rat models with destabilized medial meniscus by specifically targeting the mt-dsRNA pathway. This study presents the first instance of nanozyme-mediated mt-dsRNA hydrolysis for the control of inflammation, with the multifunctional Ce@DMSN-IMT1 system offering a synergistic therapeutic approach that holds promise as a disease-modifying strategy for OA. STATEMENT OF SIGNIFICANCE: Therapeutic targeting of mitochondrial double-stranded RNA (mt-dsRNA) to mitigate osteoarthritis (OA) progression has not been previously reported. The utilization of cerium for RNA degradation as an anti-inflammatory strategy remains undocumented. The application of mt-dsRNA release inhibitor to attenuate OA progression has not been previously documented. The dual mechanism combining mt-dsRNA degradation and release inhibition enhances anti-inflammatory effects, conferring superior therapeutic outcomes compared to traditional single-target approaches. This nanoplatform attenuates mitochondrial dysfunction and suppresses retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) signaling pathway activation. The Drug-Cerium nanozyme represents a synergistic and disease-modifying therapeutic strategy for osteoarthritis.

Biodegradable zinc (Zn)-based implants have shown great potential for orthopedic applications. However, excessive Zn²⁺ release during the degradation of Zn-based implants results in compromised biocompatibility and suboptimal osteogenic activity. Layered double hydroxides (LDHs), known for the capability to regulate degradation behavior while also exhibiting remarkable biocompatibility and osteoinductive capacity, offer a promising solution. Herein, Zn-Al LDH coating was fabricated on Zn-0.8Mg alloy substrates via an in-situ growth method. Subsequently, the effect of solution pH on the degradation behavior, cytotoxicity and osteogenic capacity of the LDH coating was investigated. Benefiting from the distinctive characteristics of the constructed LDH coating, the Zn-0.8Mg alloy with LDH coating prepared at pH=11 exhibited uniformly distributed nanosheets and demonstrated favorable corrosion resistance. During degradation, the low concentration of Zn²⁺ released from LDH-modified Zn-0.8Mg alloy implants fabricated at pH=11 improved cytocompatibility, facilitated osteoblasts proliferation and osteogenic differentiation in vitro, and accelerated bone regeneration in vivo. Furthermore, the formation mechanism of the LDH coating on Zn-based alloy was elucidated. Transcriptomic analysis further revealed that the LDH coating promoted osteogenic differentiation by activating the Wnt/β-catenin and PI3K/Akt signaling pathways. Collectively, this work offered a feasible strategy to enhance the biocompatibility and bone regeneration capability of Zn-based alloys, broadening their biomedical application. STATEMENT OF SIGNIFICANCE: As highly promising biodegradable metals, Zn-based alloys have become a research hotspot in the fields of dentistry and orthopedics. However, the excessive Zn²⁺ release during initial degradation may cause adverse biological responses, limiting their clinical translation. In this study, we fabricated LDH-coated Zn-0.8Mg alloy by in-situ growth method at different pH values to regulate degradation behavior, improve biocompatibility and enhance osteogenic properties. This study demonstrated that LDH-coated Zn-0.8Mg alloy fabricated at pH=11 exhibited significantly optimized corrosion resistance, biocompatibility and osteogenic properties, thereby expanding its potential for implant applications.

Zinc (Zn) has emerged as a promising biodegradable metal for bone tissue engineering, yet fabricating porous scaffolds via laser-based additive manufacturing (AM) remains challenging due to Zn evaporation. This study presents the successful fabrication of porous Zn scaffolds via extrusion-based AM through systematic ink formulation and sintering optimization. Printability was optimized through rheological analysis of 50-56 vol % Zn-loaded inks, while sintering conditions were refined within a precise temperature window. SEM and micro-CT characterized sintering quality and quantified pore defects. Optimal scaffolds, printed with 53 vol % ink and sintered at 415 °C for 5 h, achieved 40 ± 3% absolute porosity with minimal evaporation, attributed to a hybrid solid-liquid phase sintering mechanism. The scaffolds exhibited trabecular bone-matching mechanical properties with compressive yield strength of 16.1 ± 1.3 MPa and elastic modulus of 1.4 ± 0.1 GPa. In vitro biodegradation in r-SBF showed a corrosion rate of 0.03 ± 0.01 mm/year after 28 days, with biodegradation products including ZnO, Ca₃(PO₄)₂, and Zn-phosphate/chloride hydrates. Electrochemical tests demonstrated increasing polarization resistance (21.1 ± 3.8 kΩ·cm²) and passivation behavior. Indirect cytocompatibility assays showed > 90% metabolic activity for MC3T3-E1 cells in ≤ 50% Zn extracts, while direct seeding confirmed cell adhesion. These results establish extrusion-based AM as a viable route for fabricating Zn scaffolds with tailored porosity, controlled biodegradation, bone-like properties, and acceptable cytocompatibility, advancing the development of Zn-based biodegradable implants. STATEMENT OF SIGNIFICANCE: Although laser-based additive manufacturing of pure zinc and its alloys is becoming increasingly mature, its inherent drawbacks, such as evaporation-driven composition loss and melt-pool instabilities, remain non-negligible and underscore the need to develop and apply alternative AM strategies for Zn-based bone scaffolds. We presented an extrusion-based route to fabricate porous Zn bone scaffolds and establish an end-to-end workflow spanning ink formulation, debinding, sintering, and multi-scale characterization. By tailoring the binder system and defining a robust thermal window, we achieved high-fidelity architectures with densified struts. The resulting scaffolds displayed bone-mimicking mechanical behavior together with predictable in-vitro degradation and cytocompatibility. Our work positions extrusion-based 3D printing as a practical manufacturing platform for Zn-based biodegradable bone substitutes.

Background: The disturbed flow contributes to juxta-anastomotic intimal hyperplasia (IH) in arteriovenous fistulas (AVFs). This study developed an in vitro method aiming to understand the hemodynamic impact on endothelial cells (ECs) in AVFs.

Methods: A tubular bifurcation AVF model was constructed, and the disturbed flow was induced near the bifurcation by pulsatile flow. Hemodynamics was simulated using computational fluid dynamics (CFD) and visualized as 2D contour plots. Human Umbilical Vein Endothelial Cells (HUVECs) were cultured on a tailored polycarbonate membrane (PCM) and placed in the model. HUVECs on the PCM allowed precise mapping to the hemodynamic plots.

Results: CFD identified four regions: the outer wall with high time-averaged wall shear stress (TAWSS MAX) and transverse wall shear stress (TransWSS MAX), the inner wall with low and oscillatory wall shear stress (L/O), and the pulsatile flow (PF). HUVECs in PF were aligned in the direction of flow. The cells in other regions showed more focal adhesion junctions and fewer glycocalyces. HUVECs on inner wall had the lowest expression of Krüppel-like factor 2 and endothelial nitric oxide synthase, while the outer wall showed the highest expression of platelet-derived growth factor and transforming growth factor-β.

Conclusions: We developed an in vitro AVF model and validated the effects of different hemodynamic profiles on ECs by matching CFD plots with cell positions on a tailored PCM. This study shows that the in vitro AVF model can be a promising tool to assess the impact of interventions aimed at improving ECs function in AVFs.

Statement of significance: In Vitro Model Development: An innovative in vitro model was developed to simulate arteriovenous fistula conditions, allowing for direct assessment of endothelial cell behavior under varied hemodynamic conditions. Linking Hemodynamics to Cell Response: The research successfully correlated computational fluid dynamics results with specific endothelial cell positions, facilitating a clearer understanding of the impact of hemodynamics on cell morphology and function. Arteriovenous Fistula Failure Understanding: The study enhances the understanding of arteriovenous fistula failure mechanisms, specifically the role of intimal hyperplasia caused by disturbed flow.

Chronic liver diseases (CLDs), encompassing a spectrum from steatosis and inflammation to fibrosis, cirrhosis, represent a major global health burden, causing approximately 2 million deaths annually [1]. The management of CLDs is significantly hampered by the limitations of conventional approaches, including non-targeted drug delivery, systemic toxicity, and inadequate diagnostic sensitivity for early-stage lesions. Nanotechnology-driven biomaterial platforms have emerged as pioneering solutions to these challenges, enabling precise theranostic strategies tailored to the distinct pathophysiology of each disease stage. This review systematically elaborates on these advancements by aligning with the natural progression of CLDs [non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatitis B, liver fibrosis, and cirrhosis]. We detail how engineered platforms enhance therapeutic efficacy by achieving superior hepatic accumulation, controlled drug release, and improved metabolic, antiviral, and antifibrotic effects. Concurrently, we explore their role in diagnostics, where nanotechnology-enhanced imaging agents and nanosensors provide unprecedented sensitivity for early detection and accurate staging. By structuring the discussion around the evolving clinical needs from NAFLD and hepatitis to advanced fibrosis and cirrhosis, this review offers a stage-specific roadmap of biomaterial design principles. It aims to provide a foundational theory and forward-looking perspectives for developing next-generation, precision medicine solutions for CLDs, ultimately bridging the gap between benchtop innovation and clinical translation. STATEMENT OF SIGNIFICANCE: This review establishes a stage-specific design paradigm that bridges the gap between biomaterial innovation and the clinical continuum of chronic liver diseases (CLDs). Its significance lies in aligning cutting-edge biomaterial strategies from targeted, stimuli-responsive nanotherapeutics to engineered exosomes and gene delivery systems with the distinct pathophysiological features of each disease stage. This approach moves beyond cataloging materials to critically evaluating their translational feasibility. We analyze how rational material design addresses specific clinical bottlenecks, such as improving drug bioavailability to diseased tissue or enabling sensitive, non-invasive diagnostics for early detection. By providing this clinically focused roadmap, this review aims to accelerate the development of personalized therapies and reshape the theranostic landscape, striving to improve therapeutic outcomes of CLDs.

Zinc and its alloys emerge as promising candidates for next-generation biodegradable implants due to their acceptable biodegradability and biocompatibility, while issues such as localized corrosion and potential cytotoxicity remain to be addressed. Both issues get complicated in intestinal microenvironment with diverse microbiota, especially the effects of Zn degradation on intestinal probiotics viability. Here, Zn-0.1Li and Zn-0.2Mg alloy microwires were manufactured and investigated for their mechanical integrity, degradation behavior, and biological performance toward colorectal surgical applications as staples or self-expanding stents. Alloying with Li and Mg enhanced tensile and yield strengths via second-phase strengthening, together with markedly a more uniform and stable degradation in simulated intestinal fluid (SIF) than in Hanks' solution. The resulting steady Zn²⁺ release in SIF reduced excessive local ion accumulation. Biological assessments confirmed >80% viability of Human Umbilical Vein Endothelial cells (HUVECs) and Caco-2 cells. In particular, we found a growth-promoting effect of Zn²⁺ on Lactobacillus rhamnosus GG (LGG) (probiotics) and antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) (pathogen). Furthermore, Zn²⁺ selectively precipitated cytotoxic secondary bile acids than Mg²⁺. The integrated time-frequency analysis of electrochemical noise signals and spatio-temporal evolution of interfacial pH and O₂ levels attributed the uniform degradation of Zn alloys microwires to the strong local pH buffering effect of SIF. These findings highlight that Zn-Li and Zn-Mg microwires couple uniform degradation with cytocompatibility, antibacterial activity, and metabolites regulation, is bio-adaptive for intestinal implant applications. STATEMENT OF SIGNIFICANCE: This work demonstrates that Zn-0.1Li and Zn-0.2Mg alloy microwires showed an ultimate tensile strength of 264MPa and 199MPa. Multi-scale in operando electrochemical analyses, electrochemical impedance spectroscopy (EIS) and electrochemical noise (ECN) integrated with mapping of interfacial pH and oxygen reveals that the Zn alloy wires underwent uniform corrosion in simulated intestinal fluid (SIF) but localized corrosion in Hanks' solution. Both Zn-0.1Li and Zn-0.2Mg alloy microwires showed favorable biocompatibility with intestinal epithelial and endothelial cells, along with strong antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), and further promoted the probiotic Lactobacillus rhamnosus GG (LGG). Moreover, released Zn²⁺ ions engaged in selective coordination with secondary bile acids, thereby attenuating metabolite-induced epithelial stress. These findings highlight Zn-based alloys as promising candidates for next-generation biodegradable intestinal implants.