Extracellular Matrix Microenvironment Research Articles

Challenges in Application: Gelation Strategies of DAT-Based Hydrogel Scaffolds.

Decellularized adipose tissue (DAT) has great clinical applicability, owing to its abundant source material, natural extracellular matrix microenvironment, and nonimmunogenic attributes, rendering it a versatile resource in the realm of tissue engineering. However, practical implementations are confronted with multifarious limitations. Among these, the selection of an appropriate gelation strategy serves as the foundation for adapting to diverse clinical contexts. The cross-linking strategies under varying physical or chemical conditions exert profound influences on the ultimate morphology and therapeutic efficacy of DAT. This review sums up the processes of DAT decellularization and subsequent gelation, with a specific emphasis on the diverse gelation strategies employed in recent experimental applications of DAT. The review expounds upon methodologies, underlying principles, and clinical implications of different gelation strategies, aiming to offer insights and inspiration for the application of DAT in tissue engineering and advance research for tissue engineering scaffold development.

A Zn2+ cross-linked sodium alginate/epigallocatechin gallate hydrogel scaffold for promoting skull repair

The optimal material for repairing skull defects should exhibit outstanding biocompatibility and mechanical properties. Specifically, hydrogel scaffolds that emulate the microenvironment of the native bone extracellular matrix play a vital role in promoting osteoblast adhesion, proliferation, and differentiation, thereby yielding superior outcomes in skull reconstruction. In this study, a composite network hydrogel comprising sodium alginate (SA), epigallocatechin gallate (EGCG), and zinc ions (Zn2+) was developed to establish an ideal osteogenic microenvironment for bone regeneration. Initially, physical entanglement and hydrogen bonding between SA and EGCG resulted in the formation of a primary network hydrogel known as SA-EGCG. Subsequently, the inclusion of Zn2+ facilitated the creation of a composite network hydrogels named SA-EGCG-Zn2+ via dynamic coordination bonds with SA and EGCG. The engineered SA-EGCG2%-Zn2+ hydrogels offered an environment mimicking the native extracellular matrix (ECM). Moreover, the sustained release of Zn2+ from the hydrogel effectively enhanced cell adhesion, promoted proliferation, and stimulated osteoblast differentiation. In vitro experiments have shown that SA-EGCG2%-Zn2+ hydrogels greatly enhance the attachment and growth of osteoblast precursor cells (MC3T3-E1), while also increasing the expression of genes related to osteogenesis in these cells. Additionally, in vivo studies have confirmed that SA-EGCG2%-Zn2+ hydrogels promote new bone formation and accelerate the regeneration of bone in situ, indicating promising applications in the realm of bone tissue engineering.

All-aqueous droplets-templated tailorable core-shell alginate microspheres for constructing vascularized intestinal mucosa in vitro models

Recently, in vitro models of intestinal mucosa have become important tools for drug screening and studying the physiology and pathology of the intestine. These models enable the examination of cellular behavior in diseased states or in reaction to alterations in the microenvironment, potentially serving as alternatives to animal models. One of the major challenges in constructing physiologically relevant in vitro models of intestinal mucosa is the creation of three-dimensional microstructures that accurately mimic the integration of intestinal epithelium and vascularized stroma. Here, core–shell alginate (Alg) microspheres were generated to create the compartmentalized extracellular matrix microenvironment needed to simulate the epithelial and vascularized stromal compartments of the intestinal mucosa. We demonstrated that NIH-3T3 and human umbilical vein endothelial cells embedded in the core of the microspheres can proliferate and develop a vascular network, while human colorectal adenocarcinoma cells (Caco-2) can form an epithelial monolayer in the shell. Compared to Caco-2 monolayer encapsulated within the shell, the presence of the vascularized stroma enhances their proliferation and functionality. As such, our core–shell Alg microspheres provide a valuable method for generating in vitro models of vascularized intestinal mucosa with epithelial and vascularized stroma arranged in a spatially relevant manner and demonstrating near-physiological functionality.

O146: Investigating the cell-matrix interplay in fibrotic remodelling using renal 3D in vitro models

Abstract Introduction The dynamic biophysical microenvironment of the renal extracellular matrix is integral in regulating tissue homeostasis. Matrix remodelling is an iterative process, which guides cell behaviour and pathological fibrosis occurs due to aberrant tissue repair. Fibrosis, characterised by the desmoplastic ECM deposition and tissue stiffening, is prominent in CKD and renal carcinomas. We engineered biomimetic 3D constructs to recapitulate cell-matrix interactions in fibrotic disease progression. Methods Soft collagen-I and laminin constructs (0.2%w/v) were engineered with renal cancer cells (786-O or ACHN) or renal fibroblasts (TK188). Plastic compression was used to generate dense collagen constructs, at 6%w/v collagen density. Mechanical properties were analysed using shear rheology. Gene expression of markers defining the healthy/diseased kidney matrix was determined using qPCR. Results Over 21 days, 786-O cancer cells softened the collagen matrix. Matrix degradation was supported by collagen-I downregulation and MMP7 and vimentin upregulation. Whereas metastatic cancer cells (ACHN) stiffened the dense matrix to ∼1.25kPa, with significant gene upregulation of collagen-I, collagen-IV and LOX. Fibrotic fibroblasts soften the dense matrix by ∼1kPa, with α-SMA and MMP9 upregulation. However, matrix stiffness significantly increases with cancer cell co-cultures. Discussion Renal cancer cells remodel their biophysical environment, altering the construct’s material properties. In our models, collagen density and stromal complexity influences cell behaviour, causing alterations in biomechanics and gene expression. These models can generate physiologically relevant stiffness, enabling investigation between key cell types and the physical environment. Drugs targeting MMPs and LOX will be used to determine if we can disrupt the fibrotic remodelling.

Dysregulation of intercellular communication in vitro and in vivo via extracellular vesicles secreted by pancreatic duct adenocarcinoma cells and generated under the influence of the AG9 elastin peptide‐conditioned microenvironment

AbstractPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis due to its highly metastatic profile. Intercellular communication between cancer and stromal cells via extracellular vesicles (EVs) is crucial for the premetastatic microenvironment preparation leading to tumour metastasis. This study shows that under the influence of bioactive peptides derived from the extracellular matrix microenvironment, illustrated here by the AG‐9 elastin‐derived peptide (EDP), PDAC cells secrete more tumour‐derived EVs. Compared to PDAC‐derived EVs, tumour‐derived EVs resulting from AG‐9 treatment (PDAC AG‐9‐derived EVs) significantly stimulated cell proliferation. At constant amount, tumour‐derived EVs were similarly taken up by PDAC and HMEC‐1 cells. Tumour‐derived EVs stimulated cell proliferation, migration, proteinase secretion, and angiogenesis. Bioluminescence imaging allowed tumour‐derived EV/FLuc+ tracking in vivo in a PDAC mouse model. The biodistribution of PDAC AG‐9‐derived EVs was different to PDAC‐derived EVs. Our results demonstrate that the microenvironment, through EDP release, may not only influence the genesis of EVs but may also affect tumour progression (tumour growth and angiogenesis), and metastatic homing by modifying the in vivo biodistribution of tumour‐derived EVs. They are potential candidates for targeted drug delivery and modulation of tumour progression, and they constitute a new generation of therapeutic tools, merging oncology and genic therapy.

Dynamic relationship among extracellular matrix and body wall cells in Hirudo verbana morphogenesis

A great bulk of recent experimental evidence suggests the key role of the complex crosstalk between the extracellular matrix (ECM) and the cellular component of tissues during morphogenesis and embryogenesis. In particular, remodeling of the ECM and of its physical interactions pattern with surrounding cells represent two crucial processes that might be involved in muscle development. However, little information is available on this topic, especially on invertebrate species. To obtain new insights on how tuning the ECM microenvironment might drive cellular fate during embryonic development, we used the invertebrate medicinal leech Hirudo verbana as a valuable experimental model, due to its simple anatomy and the recapitulation of many aspects of the basic biological processes of vertebrates. Our previous studies on leech post-embryonic development have already shown the pivotal role of ECM changes during the growth of the body wall and the role of Yes-associated protein 1 (YAP1) in mechanotransduction. Here, we suggest that the interactions between stromal cell telocytes and ECM might be crucial in driving the organization of muscle layers during embryogenesis. Furthermore, we propose a possible role of the pleiotropic enzyme HvRNASET2 as a possible modulator of collagen deposition and ECM remodeling not only during regenerative processes (as previously demonstrated) but also in embryogenesis.

Microindentation of fresh soft biological tissue: A rapid tissue sectioning and mounting protocol.

Microindentation of fresh biological tissues is necessary for the creation of 3D biomimetic models that accurately represent the native extracellular matrix microenvironment. However, tissue must first be precisely sectioned into slices. Challenges exist in the preparation of fresh tissue slices, as they can tear easily and must be processed rapidly in order to mitigate tissue degradation. In this study, we propose an optimised mounting condition for microindentation and demonstrate that embedding tissue in a mixture of 2.5% agarose and 1.5% gelatin is the most favourable method of tissue slice mounting for microindentation. This protocol allows for rapid processing of fresh biological tissue and is applicable to a variety of tissue types.

Abundant nucleation sites-available liquid crystal hydrogel mimics bone ECM mineralization to boost osteogenesis

Bone extracellular matrix (ECM) is a unique organic-inorganic composite material derived from highly mineralized liquid crystal (LC) organic substrate. However, it remains a substantial challenge to design bone ECM-like LC materials with sufficient available nucleation sites to mimic the mineralization process of natural bone. Herein, we designed a bioinspired hydrogel with bone ECM-like LC organic substrate and inorganic phosphate mineralization nucleation sites for robust cell biomineralization and bone regeneration. Black phosphorus (BP) nanosheet was firstly loaded by bioactive layered double hydroxide (LDH) based on electrostatic attraction to improve the stability and photothermal performance of BP. Then, the LDH@BP was creatively added into chitin whisker/poly (ethylene glycol) diacrylate (CHW/PEGDA) LC hydrogel, abbreviated as LCgel, to fabricate LCgel/LDH@BP to highly mimic the mineralization microenvironment of bone ECM. The bone ECM-like LC topology of LCgel/LDH@BP is conducive to facilitating cell adhesion, proliferation and osteogenic differentiation. More importantly, the in-situ phosphate mineralization nucleation sites combined with mild hyperthermia induced by BP can further synergistically reinforce biomineralization of cells adhered on bone ECM-like LC substrate, thus substantially promoting cell biomineralization-mediated osteogenesis in vitro and in vivo. This study opens a new insight for the design of bioinspired hydrogel for cell biomineralization-mediated osteogenesis.

Calcium crosslinked macroporous bacterial cellulose scaffolds with enhanced in situ mineralization and osteoinductivity for cranial bone regeneration

The inherent biological inertness and lack of three-dimensional (3D) macroporous structures greatly hinder the use of pristine bacterial cellulose (BC) as a tissue engineering scaffold for bone regeneration. To address this issue, we developed a simple and effective strategy to fabricate a BC-based scaffold with excellent bioactivity and macroporous structure by crosslinking short-cut BC nanofibers using Ca2+. The Ca2+ crosslinked macroporous BC scaffold (MPBC@Ca) presents better structural stability due to the enhanced cellulose hydration. Importantly, the Ca2+ on the surface of BC nanofibers can serve as an active nucleation site to accelerate the deposition of hydroxyapatite (HAp), which is beneficial for the construction of biomimetic bone tissue extracellular matrix (ECM) microenvironment. The HAp-deposited MPBC@Ca scaffolds (HAp-MPBC@Ca) with biomimetic ECM microenvironment have excellent cytocompatibility and enhanced osteogenic differentiation of stem cells in vitro. Furthermore, the results of in vivo tests revealed that the HAp-MPBC@Ca scaffold has favorable osteoinductivity and accelerates cranial bone tissue regeneration. This study proposes a novel strategy to improve the bioactivity of BC and presents the great potential of biomimetic ECM microenvironment BC-based scaffold for repairing large cranial bone defects.

Combinatorial Microgels for 3D ECM Screening and Heterogeneous Microenvironmental Culture of Primary Human Hepatic Stellate Cells.

Nonalcoholic fatty liver disease affects 30% of the United States population and its progression can lead to nonalcoholic steatohepatitis (NASH), and increased risks for cirrhosis and hepatocellular carcinoma. NASH is characterized by a highly heterogeneous liver microenvironment created by the fibrotic activity of hepatic stellate cells (HSCs). While HSCs have been widely studied in 2D, further advancements in physiologically relevant 3D culture platforms for the in vitro modeling of these heterogeneous environments are needed. In this study, the use of stiffness-variable, extracellular matrix (ECM) protein-conjugated polyethylene glycol microgels as 3D cell culture scaffolds to modulate HSC activation is demonstrated. These microgels as a high throughput ECM screening system to identify HSC matrix remodeling and metabolic activities in distinct heterogeneous microenvironmental conditions are further employed. The 6kPa fibronectin microgels are shown to significantly increase HSC matrix remodeling and metabolic activities in single or multiple-component microenvironments. Overall, heterogeneous microenvironments consisting of multiple distinct ECM microgels promoted a decrease in HSC matrix remodeling and metabolic activities compared to homogeneous microenvironments. The study envisions this ECM screening platform being adapted to a broad number of cell types to aid the identification of ECM microenvironments that best recapitulate the desired phenotype, differentiation, or drug efficacy.

Unraveling the molecular mechanisms driving enhanced invasion capability of extravillous trophoblast cells: a comprehensive review.

Precise extravillous trophoblast (EVT) invasion is crucial for successful placentation and pregnancy. This review focuses on elucidating the mechanisms that promote heightened EVT invasion. We comprehensively summarize the pivotal roles of hormones, angiogenesis, hypoxia, stress, the extracellular matrix microenvironment, epithelial-to-mesenchymal transition (EMT), immunity, inflammation, programmed cell death, epigenetic modifications, and microbiota in facilitating EVT invasion. The molecular mechanisms underlying enhanced EVT invasion may provide valuable insights into potential pathogenic mechanisms associated with diseases characterized by excessive invasion, such as the placenta accreta spectrum (PAS), thereby offering novel perspectives for managing pregnancy complications related to deficient EVT invasion.

Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic "Cold"-"Hot" Tumor Transformations.

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.

Injectable Responsive Hydrogel Delivery Platform: Enabling High Tissue Penetration and Sonogenetic‐Like Potentiating Anti‐Tumor Immunotherapy

AbstractThe characteristics of malignant solid tumors with dense extracellular matrix (ECM) and immunosuppressive microenvironment (IME) seriously restrict the high efficacy and precise treatment of tumors, leading to increased susceptibility to malignant recurrence and metastasis. Herein, an ultrasound‐mediated hydrogel delivery platform HA‐F127@Ti‐MOF‐Au/PEG‐TK‐DOX/PFD (abbr. HFTiDP) based on a “sonogenetic‐like technology” is developed, which encapsulates sonosensitizer (Ti‐MOF‐Au), chemotherapeutic prodrug (PEG‐TK‐DOX), and ECM‐solubilizing drug pirfenidone (PFD), to achieve high tissue penetration and endogenous intracellular regulation of IME. More importantly, exogenous ultrasound stimulation combined with a hydrogel delivery platform can affect drug resistance‐related gene/protein expressions and influence signal transduction pathways in the immune microenvironment, leading to promoting TAAs release to activate immunity, achieving high efficacy in either pancreatic or triple‐negative breast cancer (TNBC), and remarkably inhibiting lung metastasis and splenomegaly. Overall, this work provides a novel strategy for an ultrasound‐mediated niche‐like delivery platform that offers high efficacy and biosafety in localized cancer therapy.

Advances in Regulating Cellular Behavior Using Micropatterns.

Micropatterns, characterized as distinct physical microstructures or chemical adhesion matrices on substance surfaces, have emerged as a powerful tool for manipulating cellular activity. By creating specific extracellular matrix microenvironments, micropatterns can influence various cell behaviors, including orientation, proliferation, migration, and differentiation. This review provides a comprehensive overview of the latest advancements in the use of micropatterns for cell behavior regulation. It discusses the influence of micropattern morphology and coating on cell behavior and the underlying mechanisms. It also highlights future research directions in this field, aiming to inspire new investigations in materials medicine, regenerative medicine, and tissue engineering. The review underscores the potential of micropatterns as a novel approach for controlling cell behavior, which could pave the way for breakthroughs in various biomedical applications.

The Interaction between Collagen 1 and High Mannose Type CD133 Up-Regulates Glutamine Transporter SLC1A5 to Promote the Tumorigenesis of Glioblastoma Stem Cells.

Targeting the niche components surrounding glioblastoma stem cells (GSCs) helps to develop more effective glioblastoma treatments. However, the mechanisms underlying the crosstalk between GSCs and microenvironment remain largely unknown. Clarifying the extracellular molecules binding to GSCs marker CD133 helps to elucidate the mechanism of the communication between GSCs and the microenvironment. Here, it is found that the extracellular domain of high mannose type CD133 physically interacts with Collagen 1 (COL1) in GSCs. COL1, mainly secreted by cancer-associated fibroblasts, is a niche component for GSCs. COL1 enhances the interaction between CD133 and p85 and activates Akt phosphorylation. Activation of Akt pathway increases transcription factor ATF4 protein level, subsequently enhances SLC1A5-dependent glutamine uptake and glutathione synthesis. The inhibition of CD133-COL1 interaction or down-regulation of SLC1A5 reduces COL1-accelerated GSCs self-renewal and tumorigenesis. Analysis of glioma samples reveals that the level of COL1 is correlated with histopathological grade of glioma and the expression of SLC1A5. Collectively, COL1, a niche component for GSCs, enhances the tumorigenesis of GSCs partially through CD133-Akt-SLC1A5 signaling axis, providing a new mechanism underlying the cross-talk between GSCs and extracellular matrix (ECM) microenvironment.

Promotion of uterine reconstruction by a tissue-engineered uterus with biomimetic structure and extracellular matrix microenvironment.

The recurrence rate for severe intrauterine adhesions is as high as 60%, and there is still lack of effective prevention and treatment. Inspired by the nature of uterus, we have developed a bilayer scaffold (ECM-SPS) with biomimetic heterogeneous features and extracellular matrix (ECM) microenvironment of the uterus. As proved by subtotal uterine reconstruction experiments, the mechanical and antiadhesion properties of the bilayer scaffold could meet the requirement for uterine repair. With the modification with tissue-specific cell-derived ECM, the ECM-SPS had the ECM microenvironment signatures of both the endometrium and myometrium and exhibited the property of inducing stem cell-directed differentiation. Furthermore, the ECM-SPS has recruited more endogenous stem cells to promote endometrial regeneration at the initial stage of repair, which was accompanied by more smooth muscle regeneration and a higher pregnancy rate. The reconstructed uterus could also sustain normal pregnancy and live birth. The ECM-SPS may thereby provide a potential treatment for women with severe intrauterine adhesions.

SDC1 and ITGA2 as novel prognostic biomarkers for PDAC related to IPMN

The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package ‘limma.’ A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable survival prognosis was demonstrated by SDC1 and ITGA2, which were highly expressed during in vitro PDAC cell proliferation, apoptosis, and migration. SDC1high was enriched in interferon alpha (IFN-α) response and ITGA2high was primarily detected in epithelial-mesenchymal transition (EMT), which was verified using western blotting. We concluded that SDC1 and ITGA2 are potential prognostic biomarkers for PDAC associated with IPMN. Downregulation of SDC1 and ITGA2 expression in PDAC occurs via a mechanism involving possible regulation of IFN-α response, EMT, and immunity, which may act as new targets for PDAC therapy.

Fibroblasts alter the physical properties of dermal ECM-derived hydrogels to create a pro-angiogenic microenvironment

This study aimed to investigate the impact of fibroblasts (MRC-5) on the extracellular matrix (ECM) microenvironment of endothelial cells (ECs) during the vascularization of skin-derived ECM hydrogel in vitro. Two types of ECs were studied: human dermal microvascular endothelial cells (HMEC) and human pulmonary microvascular endothelial cells (HPMEC). Results showed that the presence of MRC-5 fibroblasts increased the stiffness of the hydrogel and led to larger fiber diameters and increased porosity. Extensive collagen fiber remodeling occurred in the ECM hydrogel with MRC-5 fibroblasts. Additionally, higher levels of fibulin-1 and fibronectin were deposited in the hydrogel when co-cultured with MRC-5 fibroblasts. These findings suggest that MRC-5 fibroblasts play a role in modifying the ECM microenvironment, promoting vascularization through dynamic ECM remodeling.

UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer

BackgroundEpithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH).MethodsImmunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined.ResultsHigh UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. High UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH high TIC population. Conversely, overexpression of UGDH in the C4/Differentiated subtype reduced the TIC population. In co-culture models, UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins, and fibroblast collagen production. Inflammatory cytokine expression of spheroids was altered by UGDH expression. The effect of UGDH knockdown or overexpression in the C1/ Mesenchymal and C4/Differentiated subtypes respectively was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH improved survival and reduced tumor burden in C1/Mesenchymal compared to controls.ConclusionsThese data show that modulation of UGDH expression in ovarian cancer reveals distinct roles for UGDH in the C1/Mesenchymal and C4/Differentiated molecular subtypes of EOC, influencing the tumor microenvironmental composition. UGDH is a strong potential therapeutic target in TICs, for the treatment of EOC, particularly in patients with the mesenchymal molecular subtype.

Cartilage-inspired self-assembly glycopeptide hydrogels for cartilage regeneration via ROS scavenging

Cartilage injury represents a frequent dilemma in clinical practice owing to its inherently limited self-renewal capacity. Biomimetic strategy-based engineered biomaterial, capable of coordinated regulation for cellular and microenvironmental crosstalk, provides an adequate avenue to boost cartilage regeneration. The level of oxidative stress in microenvironments is verified to be vital for tissue regeneration, yet it is often overlooked in engineered biomaterials for cartilage regeneration. Herein, inspired by natural cartilage architecture, a fibril-network glycopeptide hydrogel (Nap-FFGRGD@FU), composed of marine-derived polysaccharide fucoidan (FU) and naphthalenephenylalanine-phenylalanine-glycine-arginine-glycine-aspartic peptide (Nap-FFGRGD), was presented through a simple supramolecular self-assembly approach. The Nap-FFGRGD@FU hydrogels exhibit a native cartilage-like architecture, characterized by interwoven collagen fibers and attached proteoglycans. Beyond structural simulation, fucoidan-exerted robust biological effects and Arg-Gly-Asp (RGD) sequence-provided cell attachment sites realized functional reinforcement, synergistically promoted extracellular matrix (ECM) production and reactive oxygen species (ROS) elimination, thus contributing to chondrocytes-ECM harmony. In vitro co-culture with glycopeptide hydrogels not only facilitated cartilage ECM anabolic metabolism but also scavenged ROS accumulation in chondrocytes. Mechanistically, the chondro-protective effects induced by glycopeptide hydrogels rely on the activation of endogenous antioxidant pathways associated with nuclear factor erythroid 2-related factor 2 (NRF2). In vivo implantation of glycopeptide hydrogels successfully improved the de novo cartilage generation by 1.65-fold, concomitant with coordinately restructured subchondral bone structure. Collectively, our ingeniously crafted bionic glycopeptide hydrogels simultaneously rewired chondrocytes’ function by augmenting anabolic metabolism and rebuilt ECM microenvironment via preserving redox equilibrium, holding great potential for cartilage tissue engineering.