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Osteoarthritis (OA) presents a significant therapeutic challenge, with few options for preserving joint cartilage and repairing associated tissue damage. Inflammation is a pivotal factor in OA-induced cartilage deterioration and synovial inflammation. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (HucMSCs) have gained recognition as a promising noncellular therapeutic modality, but their use is hindered by the challenge of harvesting a sufficient number of exosomes with effective therapeutic efficacy. Given that HucMSCs are highly sensitive to microenvironmental signals, we hypothesized that priming HucMSCs within a proinflammatory environment would increase the number of exosomes secreted with enhanced anti-inflammatory properties. Subsequent miRNA profiling and pathway analysis confirmed that interleukin-1 beta (IL-1β)-induced exosomes (C-Exos) exert positive effects through miRNA regulation and signaling pathway modulation. In vitro experiments revealed that C-Exos enhance chondrocyte functionality and cartilage matrix production, as well as macrophage polarization, thereby enhancing cartilage repair. C-Exos were encapsulated in hyaluronic acid hydrogel microspheres (HMs) to ensure sustained release, leading to substantial improvements in the inflammatory microenvironment and cartilage regeneration in a rat OA model. This study outlines a strategy to tailor exosome cargo for anti-inflammatory and cartilage regenerative purposes, with the functionalized HMs demonstrating potential for OA treatment.

Regeneration of the injured endometrium, particularly the functional layer, is crucial for the prevention of uterine infertility. At present, clinical treatment using sodium hyaluronate hydrogel injection is limited by its relatively low fluidity, short-term retention, and insufficient bioactive ingredients, so it is necessary to develop an advanced healing-promoting hydrogel. The modulation of the microenvironment by Lactobacillus presents a bioactive component that can facilitate the regeneration of the functional layer. Our study introduces a multifunctional Lactobacillus -loaded poly( N -isopropylacrylamide)-grafted bacterial cellulose (BC- g -PN@L) hydrogel designed with superior injectability and in situ stability. At 25 °C (room temperature), a uniform distribution is achieved with a low injection pressure of only 7.90 kPa. At 37 °C (body temperature), the BC- g -PN@L hydrogel forms a robust three-dimensional nanonetwork, providing space and substance exchange channels for Lactobacillus to maintain its viability and bioactivity. Enhanced by the hydrophobic isopropyl groups in poly( N -isopropylacrylamide) side chains and the rigid bacterial cellulose substrates, the BC- g -PN@L hydrogel exhibits prolonged retention properties in the uterine cavity, persisting for over 21 days. These attributes endow the BC- g -PN@L hydrogel with versatile pro-healing capacity and microenvironment modulation in a rat model of endometrial injury. Our BC- g -PN@L hydrogel promotes the development of advanced injectable hydrogels to facilitate both histological and functional repair of the injured endometrium.

Hydrogels are promising wound dressings due to their extracellular matrix-like properties and tunable structure-function characteristics. Besides the physical isolation effect, hydrogel dressings are highly expected to possess tissue-adhesive performance and antibacterial capacity, which are beneficial for their clinical translations. Herein, a guar gum (GG)-based nanocomposite hydrogel was fabricated by mixing methacrylated GG (GGMA), acrylic acid, acrylated 3-aminophenylboronic acid, mangiferin (MF)-loaded cetyltrimethyl ammonium chloride (CTAC) micelles (MF@CTAC) and radical initiator. This hydrogel exhibited stable and tunable mechanical property as well as excellent biocompatibility. Borate crosslinking and physical interactions of the hydrogel produced a certain degree of self-healing ability, good tissue adhesive and hemostatic capacity. MF endowed the hydrogel with good antioxidant ability and excellent synergistic antibacterial ability with CATC. In vivo experiments indicated that the hydrogel significantly accelerated wound healing with a narrower wound edge, thicker granulation tissue, maturer epidermis and dermis tissue, higher collagen deposition level, milder inflammatory response, and enhanced angiogenesis. The hydrogel without adding antibiotics and other exogenous active ingredients showed great application potential as a versatile wound dressing material., Competing Interests: Declaration of competing interest The authors declare no competing financial interests and personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Spinal cord injury (SCI) is a devastating condition without effective therapy currently available. The inflammatory cascade following SCI leads to neuronal apoptosis and glial cell activation. The utilization of local injectable hydrogels with immunotherapy drugs directly into injured nerve tissues represents a promising therapeutic strategy. Herein, injectable hydrogels grafted with clickable methylprednisolone (MP) and cellular adhesion peptide were developed using free radical polymerization for promoting nerve regeneration following SCI. MP conjugated hydrogels could modulate the immunoinflammatory microenvironment of SCI and sustain neuron survival. The multi-stiffness hydrogels were fabricated by adjusting concentration ratios to evaluate appropriate mechanical stimuli. In a model of dorsal root ganglion, MP grafted hydrogels with mechanical signals similar to those of adult rat spinal cords demonstrated superior efficacy in promoting dorsal root ganglion growth. MP grafted hydrogels could regulate the immune-inflammatory microenvironment, promote recovery of both motor function and sensory functions. The positive findings suggested that the interplay between immunomodulation and mechanical signals plays a crucial role in promoting nerve regeneration, indicating significant potential for hydrogels as a therapeutic approach for repairing SCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Delayed healing due to the persistent microenvironment disorder caused by the hyperglycemia and persistent inflammatory reaction is a core pathological characteristic of diabetic wound. Topical microenvironment modulation represents an important avenue to address delayed healing issue. Microneedles are powerful tools for topical microenvironment modulation as they can effectively deliver therapeutic ingredients into the shallow surface layer of the wound based on their depth-limited tissue penetration capability. Herein, a hybrid microneedle composed of carvacrol (CV), cyclodextrin (CD), mesoporous ceria nanoparticles (MCNs) and hyaluronate (HA) is constructed with objective to modulate the microenvironment within the diabetic wound. The hybrid microneedle is constructed via a two-stage process comprising three stepwise embedding procedures in the first stage and four microneedle casting procedures in the second stage. The physical, chemical and antibacterial performances, as well as the in vitro and in vivo therapeutic potentials, of the hybrid microneedle are evaluated. The therapeutic ingredients, mainly CV and MCNs, incorporated in the microneedle can be readily released into the diabetic wound, and effective microenvironment modulation is realized through the designed antibacterial, antioxidant and anti-inflammatory functions. Consequently, the tissue reconstruction processes including cell proliferation and migration, angiogenesis, and collagen deposition are accelerated due to the improved microenvironment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The progression of intervertebral disc degeneration (IVDD) is associated with increased cell apoptosis and reduced extracellular matrix (ECM) production, both of which are driven by ongoing inflammation. Thus, alleviating the acidic inflammatory microenvironment and mitigating the apoptosis of nucleus pulposus cells (NPCs) are essential for intervertebral disc (IVD) regeneration. Regulating pH levels in the local environment can reduce inflammation and promote tissue recovery. In this study, a lactic acid-capturing microgel carrying a functionalized miRNA-155 nanocarrier was designed for IVD regeneration. microRNA-155 was loaded into the NPC-targeted nanogel via host-guest binding. The miR-155 nanocarrier (NGM) achieved lactic acid-sensitive release of miRNA-155, resulting in rapid regulation of apoptosis. Moreover, SS31, which dissociated from the nanogel network, had the ability to regulate mitochondrial metabolism. Moreover, the microgel was constructed using a matrix metalloproteinase-responsive peptide. The chitosan coating on the microgel system was ingeniously employed to capture lactic acid and enable pH-responsive dissociation, thereby alleviating the acidic microenvironment to protect cell viability and facilitate the delivery of the NGM. The microgel system effectively promoted IVD regeneration by alleviating the acidic microenvironment and preventing NPC apoptosis.

Microrobots are poised to transform biomedicine by enabling precise, noninvasive procedures. However, current magnetic microrobots, composed of solid monolithic particles, present fundamental challenges in engineering intersubunit interactions, limiting their collective effectiveness in navigating irregular biological terrains and confined spaces. To address this, we design hierarchically assembled microrobots with multiaxis mobility and collective adaptability by engineering the potential magnetic interaction energy between subunits to create stable, self-reconfigurable structures capable of carrying and protecting cargo internally. Using double emulsion templates and magnetic control techniques, we confine 10 nm iron oxide and 15 nm silica nanoparticles within the shell of 100 μm microcapsules that form multiunit robotic collectives. Unexpectedly, we find that asymmetric localization of iron oxide nanoparticles in the microcapsules enhances the intercapsule potential energy, creating stable connections under rotating magnetic fields without altering the magnetic susceptibility. These robotic microcapsule collectives exhibit emergent behaviors, self-reconfiguring into kinematic chain-like structures to traverse complex obstacles, arched confinements, and adhesive, rugged biological tissues that typically impede microscale systems. By harnessing these functions, we demonstrate targeted antifungal delivery using a localized biofilm model on mucosal tissues, showing effective killing of Candida without binding or causing physical damage to host cells. Our findings show how hierarchical assembly can produce cargo-carrying microrobots with collective, self-adaptive mobility for traversing complex biological environments, advancing targeted delivery for biomedical applications.

Hypoxia, high ROS levels and chronic inflammation are the main factors that hinder the healing of diabetic wounds. Long-term exposed wounds are prone to bacterial infection, especially MRSA infection, which exacerbates the complex wound microenvironment of diabetes and threatens patients' lives. Here, we developed a ROS nanopurifier (CSVNP), which was prepared by loading superoxide dismutase (SOD), catalase (CAT) and vancomycin into nanogels through in-situ polymerization. CSVNP can effectively increase enzyme loading and stability, and improve cascade reaction efficiency between enzymes through nanosize effect, so that CSVNP can use a variety of ROS (H 2 O 2 and ·O 2 - ) as oxygen sources to generate much oxygen in situ, which can effectively alleviate the hypoxic environment and inflammatory response of diabetic tissues, theraby promoting cell migration and angiogenesis, and accelerating wound healing. In addition, the generated oxygen can further promote the transformation of pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages and reduce pro-inflammatory factors (TNF-α, IL-6, and IL-1β) release. CSVNP can also effectively eradicate MRSA by releasing vancomycin, preventing bacterial infection from exacerbating the deterioration of diabetic wounds. This multifunctional ROS nanopurifier with antiphlogosis, antibacterial and in-situ oxygen supply, provides a new strategy with universal and translational prospects for clinical diabetic tissue damage. STATEMENT OF SIGNIFICANCE: Methicillin-resistant staphylococcus aureus (MRSA)-infected diabetic wounds face significant challenges in clinical care, characterized by high ROS levels, acute inflammation, vascular lesions, and hypoxia, which impede healing and risk severe complications. Here, we originally developed a reactive oxygen species (ROS) nanopurifier prepared by in-situ polymerization of superoxide dismutase (SOD), catalase (CAT), and vancomycin. It uses SOD and CAT to continuously convert ROS (H 2 O 2 and ·O 2 - ) into O 2 in diabetic tissues, effectively improving hypoxia and chronic inflammation, thereby promoting angiogenesis and cell proliferation and migration, and accelerating diabetic wound healing. Vancomycin can effectively kill MRSA bacteria, avoid bacterial infection spread, and reduce complications risk. This safe, efficient and easy-to-prepare ROS nanopurifier provides a general strategy for repairing MRSA-infected diabetic tissue damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Inc. All rights reserved.)

Background: Ischemia-reperfusion injury is a common cause of cardiovascular and cerebrovascular diseases. The reoxygenation during reperfusion leads to an overproduction of reactive oxygen species (ROS). As an antioxidant, H 2 S can scavenge ROS to inhibit oxidative stress and inflammatory reaction, thus attenuating ischemia-reperfusion injury. In this process, the changes of cellular microenvironment (polarity or viscosity) have not been fully discussed. In order to real-time track the changes of cellular microenvironment during the treatment of ischemia-reperfusion injury with H 2 S. It is necessary to develop highly selective and sensitive probes that can cascade response to hydrogen sulfide and cellular microenvironment., Results: We designed and synthesized a fluorescent probe TPEC-DNBS which can produce cascade response to H 2 S and microenvironment. An intermediate TPEC-OH is produced after highly selective and sensitive response to H 2 S, which can further respond to polarity and viscosity. In addition, due to the aggregation-induced emission (AIE) and twisted intramolecular charge transfer (TICT) effects, polarity can promote the fluorescence emission wavelength and intensity of TPEC-OH to produce double response characteristics, and its change trend (from weak green fluorescence at low polarity to strong red fluorescence at high polarity) is opposite to that of traditional polar probes (from strong green fluorescence at low polarity to weak red fluorescence at high polarity). Viscosity can only induce the change of fluorescence intensity. By constructing the cardiomyocyte model and hepatocyte model of ischemia-reperfusion, we further prove that after ischemia-reperfusion injury, the cells are in an environment of low polarity, and the microenvironment can be recovered after H 2 S treatment., Significance: An AIE-TICT fluorescence probe capable of cascading responses to H 2 S, polarity and viscosity was constructed by using tetraphenylethylene and coumarin moieties. This probe provides a more intuitive and convenient condition for real-time tracking the changes of cellular microenvironment (polarity or viscosity) before and after H 2 S treatment of ischemia-reperfusion injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: It is well established that the interaction between osteogenesis and inflammation can impact bone tissue regeneration. The use of nanoparticles to treat and alleviate inflammation at the molecular level has the potential to improve the osteogenic microenvironment and serve as a therapeutic approach., Methods: We have synthesized new hollow cerium oxide nanoparticles and doped with cathepsin B inhibitor (CA-074Me) to create novel h CeO 2 @CA-074Me NPs. We characterized the surface morphology and physicochemical properties of h CeO 2 @CA-074Me NPs. Macrophage RAW 264.7 was cultured with h CeO 2 @CA-074Me NPs using P. gingivalis- LPS ( P.g -LPS) stimulation as a model of inflammation. RT-PCR and Western blot analysis was employed to evaluate the effects of h CeO 2 @CA-074Me NPs on macrophage phenotype and the CTSB-NLRP3 signaling pathway. To further investigate the inflammatory osteogenic microenvironment, MC3T3-E1 cells were cultured with P.g -LPS to create an in vitro osteogenic conditions under inflammation. The cells were then co-cultured with h CeO 2 @CA-074Me NPs for 7, 14, and 21 d. The osteogenic ability was evaluated using ALP staining, ALP quantitative analysis, alizarin red staining, and RT-PCR analysis., Results: Findings clearly demonstrated that h CeO 2 @CA-074Me NPs could effectively reduce the production of ROS and inhibited CTSB-NLRP3 signal pathway, thereby significantly attenuating the damage caused by the cellular inflammatory response. h CeO 2 @CA-074Me NPs could also induce the polarization of macrophages towards anti-inflammatory M2 phenotype. Additionally, results confirmed that h CeO 2 @CA-074Me NPs could inhibit inflammation and ameliorate osteogenic microenvironment, thus promoting the osteogenesis of MC3T3-E1 cells., Conclusion: The synthetic h CeO 2 @CA-074Me NPs could able to modify the osteogenic microenvironment under inflammatory conditions by simultaneously inhibiting the CTSB-NLRP3 signaling pathway and regulating the macrophage phenotype through their ability to scavenge ROS. Based on these findings, our study may offer a promising approach for managing inflammatory bone damage., Competing Interests: The authors declare that they have no competing interests in this work., (© 2025 Niu et al.)

Osteoarthritis (OA) is a progressively developing condition primarily characterized by the deterioration of articular cartilage and the proliferation of bone, along with ongoing inflammation. Although the precise pathogenesis remains somewhat elusive, restoring the homeostatic balance of the intra-articular microenvironment is crucial for the management of OA. Intra-articular injection of medication is one of the most direct and effective treatment methods; however, most injectable drugs used for osteoarthritis treatment, due to their rapid breakdown, quick release, poor biological activity, and frequent injections, leading to increased risk of infection and suboptimal therapeutic outcomes. In this study, a lubricating and dual-responsive injectable hydrogel based on zeolitic imidazolate frameworks-8 (ZIF-8) impregnated with Quercetin (Que) is designed, which can facilitate OA treatment by remodeling the microenvironment. The prepared injectable nanocomposite hydrogel (MH/CCM@ZIF-8@Que) exhibits pH and reactive oxygen species (ROS) responsiveness, alongside a controllable release of bioactive substances to modulate the microenvironment of bone tissue, thereby mitigating synovitis and the degeneration of cartilage matrix, while simultaneously facilitating cartilage repair. This developed thermosensitive injectable hydrogel, which effectively balances lubrication with the controlled release of bioactive substances, represents a highly promising therapeutic approach for osteoarthritis., (© 2024 Wiley‐VCH GmbH.)

Current clinical strategies for the treatment of temporomandibular joint osteoarthritis (TMJOA) primarily target cartilage biology, overlooking the synergetic effect of various cells and inorganic components in shaping the arthritic microenvironment, thereby impeding the effectiveness of existing therapeutic options for TMJOA. Here, γ-Fe 2 O 3 @TA@ALN magnetic nanoparticles (γ-Fe 2 O 3 @TA@ALN MNPs) composed of γ-Fe 2 O 3 , tannic acid (TA), and alendronate sodium (ALN) are engineered to reconstruct the osteoarthritic microenvironment and mitigate TMJOA progression. γ-Fe 2 O 3 @TA@ALN MNPs can promote chondrocytes' proliferation, facilitate chondrogenesis and anisotropic organization, enhance lubrication and reduce cartilage wear, and encourage cell movement. Magnetic-responsive γ-Fe 2 O 3 @TA@ALN MNPs also exhibit pH sensitivity, which undergoes decomposition within acidic environment to release ALN on demand. Under a 0.2 T static magnetic field, γ-Fe 2 O 3 @TA@ALN MNPs accelerate the synthesis of cartilage-specific proteins, and suppress catabolic-related genes expression and reactive oxygen species generation, affording additional protection to TMJ cartilage. In TMJOA mouse models, articular injection of γ-Fe 2 O 3 @TA@ALN MNPs effectively alleviates cartilage degeneration and subchondral bone loss in short and long terms, offering promising avenues for the development of therapeutic interventions for TMJOA., (© 2024 Wiley‐VCH GmbH.)

Allergic diseases are a group of chronic inflammatory disorders driven by abnormal immune responses. Dendritic cells (DCs) play a pivotal role in the initiation and progression of allergic diseases by modulating T cell responses. Extensive progress has been made in characterizing crucial roles of metabolic reprogramming in the regulation of immune cell functions. As the critical upstream regulators and effectors in allergic responses, the activation, migration, and function of DCs are reliant on metabolic reprogramming. In this review, we summarize the metabolic characteristics of DCs, and how the cellular microenvironment shapes DC function. We also elucidate the metabolic regulation of DC biology in the context of allergic diseases and targeted therapeutic strategies based on DC metabolism regulation. Understanding the functional alterations in DCs during allergic responses and the underlying mechanisms governing its metabolic regulation is crucial for the development of effective strategies for the prevention and treatment of allergic diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The multi-biological barriers present in the inflammatory microenvironment severely limit the targeted aggregation of anti-inflammatory drugs in the lesion area. However, conventional responsive drug carriers inevitably come into contact with several pro-responsive stimulatory mediators simultaneously, leading to premature drug release and loss of most therapeutic effects. Breaking through the multi-level barriers of the inflammatory microenvironment is essential to improve the enrichment and bioavailability of drugs., Results: In this study, we propose a novel two-stage structural strategy to build shielded cascades of targeted nanocarriers (FA-PTP@Que) through inflammatory mediators, using cascade structures to cross multiple environmental barriers. The cascade structure of FA-PTP@Que is responsive to inflammatory mediators and exhibits ideal pathological microenvironmental response and drug release properties. FA-PTP@Que has shown good macrophage regulation and anti-inflammatory effects by efficiently targeting macrophages, scavenging intracellular reactive oxygen species (ROS), and down-regulating the secretion of pro-inflammatory factors. Significantly, in mice with arthritis and colitis, FA-PTP@Que enriches and targets macrophages at the sites of arthritis and colitis, showing significant anti-inflammatory effects., Conclusion: FA-PTP@Que combines active chemotaxis of nanocarriers to inflammatory tissues and active targeting of effector cells, acting precisely at each barrier level in different microenvironments by responding to inflammatory mediators and overcoming the multiple barriers in the inflammatory microenvironment. This innovative strategy can effectively break through various inflammatory microenvironments and has the potential application to other inflammatory diseases., Competing Interests: Declarations. Ethics approval and consent to participate: The animal handling and surgical procedures were conducted by the protocols approved by the Ethics Committee of the Affiliated Stomatological Hospital of Chongqing Medical University (2022(No. 064)). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Inflammation often causes irreversible damage to dental pulp tissue. Dental pulp stem cells (DPSCs), which have multidirectional differentiation ability, play critical roles in the repair and regeneration of pulp tissue. However, the presence of proinflammatory factors can affect DPSCs proliferation, differentiation, migration, and other functions. LL-37 is a natural cationic polypeptide that inhibits lipopolysaccharide (LPS) activity, enhances cytokine production, and promotes the migration of stem cells. However, the potential of LL-37 in regenerative endodontics remains unknown. This study aimed to investigate the regulatory role of LL-37 in promoting the migration and odontogenic differentiation of DPSCs within an inflammatory microenvironment. These findings establish an experimental foundation for the regenerative treatment of pulpitis and provide a scientific basis for its clinical application., Materials and Methods: DPSCs were isolated via enzyme digestion combined with the tissue block adhesion method and identified via flow cytometry. The impact of LL-37 on the proliferation of DPSCs was evaluated via a CCK-8 assay. The recruitment of DPSCs was assessed through a transwell assay. The mRNA expression levels of inflammatory and aging-related genes were assessed via reverse transcription‒polymerase chain reaction (RT‒PCR), western blotting, and enzyme‒linked immunosorbent assay (ELISA). The odontogenic differentiation of DPSCs was assessed through alkaline phosphatase (ALP) staining, alizarin red staining, and RT‒PCR analysis., Results: LL-37 has the potential to enhance the migration of DPSCs. In an inflammatory microenvironment, LL-37 can suppress the expression of genes associated with inflammation and aging, such as TNF-α, IL-1β, IL-6, P21, P38 and P53. Moreover, it promotes odontogenic differentiation in DPSCs by increasing ALP activity, increasing calcium nodule formation, and increasing the expression of dentin-related genes such as DMP1, DSPP and BSP., Conclusion: These findings suggest that the polypeptide LL-37 facilitates the migration of DPSCs and plays a crucial role in resolving inflammation and promoting cell differentiation within an inflammatory microenvironment. Consequently, LL-37 has promising potential as an innovative therapeutic approach for managing inflammatory dental pulp conditions., Competing Interests: Declarations. Ethical approval and consent to participate: The extraction procedures of human DPSCs were conducted in accordance with the Declaration of Helsinki, and informed consent was obtained from the donors and/or their guardians before the tooth collection. The extraction procedures of human DPSCs in this study were approved by the Ethics Committee of Anhui Medical University. (Project title: The key physicochemical factors and mechanisms of collagen intra/extra-fibrillar mineralization mediated by polyelectrolyte-calcium phosphate prenucleation clusters; Approval No: LLSC20240974; Date of approval: 2024–03-01). Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Chronic wounds, frequently arising from conditions like diabetes, trauma, or chronic inflammation, represent a significant medical challenge due to persistent inflammation, heightened infection risk, and limited treatment solutions. This study presents a novel bioengineered approach to promote tissue repair and improve the healing environment. We developed a bioactive hydrogel patch, encapsulated zeolitic imidazolate framework-8 (ZIF-8) into extracellular vesicles (EVs) derived from anti-inflammatory M2 macrophages, and synthesized ZIF@EV, then embedded it in the sodium alginate matrix. This hydrogel structure enables the controlled release of therapeutic agents directly into the wound site, where it stimulates endothelial cell proliferation and promotes new blood vessel formation. These processes are key components of effective tissue regeneration. Crucially, the EV-infused patch influences the immune response by polarizing macrophages towards an M2 phenotype, shifting the wound environment from inflammation toward regenerative healing. When applied in a murine model of chronic wounds, the EV hydrogel patch demonstrated notable improvements in healing speed, quality, and tissue integration compared to traditional approaches such as growth factor therapies and foam dressings. These promising findings suggest that this bioactive hydrogel patch could serve as a versatile, practical solution for chronic wound management, providing an adaptable platform that addresses both the biological and logistical needs of wound care in clinical settings.

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury., Competing Interests: Declarations. Ethics Approval and Consent to Participate: The animal study protocol was approved by the Ethics Committee of Xiamen University (approval no. XMULAC2023052) and conducted in accordance with the Guide for the Care and Use of Laboratory Animals ( https://www.ncbi.nlm.nih.gov/books/NBK54050/ ). Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Liver fibrosis represents an inevitable stage of various chronic liver diseases. The activated hepatic stellate cells (aHSCs) are the main drivers for promoting the development of liver fibrosis. Meanwhile, liver macrophages can secrete pro-inflammatory cytokines, thus accelerating the deterioration of the liver. Regulating both aHSCs and the inflammatory microenvironment in the liver simultaneously may be an effective strategy for treating liver fibrosis. A multi-pronged nano-bioconjugated system, HNP-B-aEV, was developed according to the above strategy. Based on cell aggregate-derived extracellular vesicles (aEVs) and hydroxychloroquine (HCQ)-loaded nanoparticles (HNP) modified with retinol, HNP-B-aEV is prepared via a reactive oxygen species (ROS)-responsive boronate linker. In the ROS-rich microenvironment of liver fibrosis, aEVs and HNP are released, eliminating ROS, and targeting aHSCs and macrophages respectively to inhibit the activation of HSCs. Both in vitro and in vivo studies demonstrated that HNP-B-aEV can significantly inhibit the release of inflammatory factors from M1 macrophages, remodeling the microenvironment and preventing the activation of HSCs, offering a multi-pronged treatment for liver fibrosis. This strategy can inhibit the progression of liver fibrosis at its source, providing a new perspective for the clinical treatment of liver fibrosis., Competing Interests: Declaration of competing interest All authors have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is exacerbated by injurious mechanical forces that destabilize the pulmonary mechanical microenvironment homeostasis, leading to alveolar dysfunction and exacerbating disease severity. However, given the inherent mechanosensitivity of fibrotic lungs, where type II alveolar epithelial cells (AEC IIs) are subjected to persistent stretching and overactivated myofibroblasts experience malignant interactions during mechanotransduction, it becomes imperative to develop effective strategies to modulate the pulmonary mechanical microenvironment. Herein, cyclo (RGDfC) peptide-decorated zeolitic imidazolate framework-8 nanoparticles (named ZDFPR NPs) are constructed to target and repair the aberrant mechanical force levels in pathological lungs. Specifically, reduces mechanical tension in AEC IIs by pH-responsive ZDFPR NPs that release zinc ions and 7, 8-dihydroxyflavone to promote alveolar repair and differentiation. Meanwhile, malignant interactions between myofibroblast contractility and extracellular matrix stiffness during mechanotransduction are disrupted by the fasudil inhibition ROCK signaling pathway. The results show that ZDFPR NPs successfully restored pulmonary mechanical homeostasis and terminated the fibrosis process in bleomycin-induced fibrotic mice. This study not only presents a promising strategy for modulating pulmonary mechanical microenvironment but also pioneers a novel avenue for IPF treatment., (© 2024 Wiley‐VCH GmbH.)

Wound management is crucial yet imposes substantial social and economic burdens on patients and healthcare systems. The recent rapid advancements in biomaterials and manufacturing technology have created favorable conditions for expediting wound healing. This review examines the latest developments in biomacromolecule-based wound dressings, with a particular focus on proteins and polysaccharides, and their role in modulating the wound microenvironment. The importance of extracellular matrix (ECM)-inspired materials, such as hydrogels and biomimetic dressings, is emphasized. Additionally, this review explores the functionalization of wound dressings, emphasizing properties such as hemostatic capabilities, pain relief, antimicrobial activity, and innovative smart functions like electroceuticals and wound condition monitoring. The study integrates discussions on both the macroscopic healing outcomes and the microscopic pathophysiological mechanisms, highlighting recent advances in managing wound environments to expedite healing. Finally, the review critically assesses the challenges associated with the clinical translation of these wound-healing materials in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Diabetic wound healing faces several complex challenges, such as hypoxia, oxidative stress, and bacterial infections, which severely inhibit the wound-healing process. Herein, a quaternary ammonium salt-crosslinked carboxymethyl chitosan hydrogel (TPC) with excellent antioxidant and antibacterial properties was developed to immunoregulate the diabetic wound microenvironment. The TPC hydrogel was prepared by first mixing carboxymethyl chitosan (CMCS) and protocatechualdehyde (PA), followed by the addition of a quaternary ammonium cross-linker (TSPBA) and a superoxide dismutase (SOD)-catalase (CAT) cascade system. The immobilized SOD and CAT retained their activity, continuously converting endogenous ·O 2 - and H 2 O 2 to O 2 and H 2 O. PA also provided the TPC hydrogel excellent oxygen and nitrogen radical scavenging capacity. The quaternary ammonium groups in TSPBA significantly enhanced the inherent antibacterial ability of CMCS-based hydrogels. In diabetic wound-healing experiments, this porous and adhesive TPC hydrogel effectively closed wounds and regenerated skin tissue, resulting in shorter wound edges, thicker granulation, and higher collagen deposition levels compared with other groups. The TPC hydrogel also promoted macrophage polarization toward the M2 phenotype, accelerating wound healing by upregulating IL-10 expression, downregulating IL-6 expression, and enhancing angiogenesis. These results demonstrate the great potential of TPC hydrogel as a promising therapeutic dressing for treating diabetic wounds., Competing Interests: Declaration of competing interest The authors declare no competing financial interests and personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatic fibrosis progresses concomitantly with a variety of biomechanical alternations, especially increased liver stiffness. These biomechanical alterations have long been considered as pathological consequences. Recently, growing evidence proposes that these alternations result in the fibrotic biomechanical microenvironment, which drives the activation of hepatic stellate cells (HSCs). Here, an inorganic ascorbic acid-oxidase (AAO) mimicking nanozyme loaded with liquiritigenin (LQ) is developed to trigger remodeling of the fibrotic biomechanical microenvironment. The AAO mimicking nanozyme is able to consume intracellular ascorbic acid, thereby impeding collagen I deposition by reducing its availability. Simultaneously, LQ inhibits the transcription of lysyl oxidase like 2 (LOXL2), thus impeding collagen I crosslinking. Through its synergistic activities, the prepared nanosystem efficiently restores the fibrotic biomechanical microenvironment to a near-normal physiological condition, promoting the quiescence of HSCs and regression of fibrosis. This strategy of remodeling the fibrotic biomechanical microenvironment, akin to "pulling the rug out from under", effectively treats hepatic fibrosis in mice, thereby highlighting the importance of tissue biomechanics and providing a potential approach to improve hepatic fibrosis treatment., (© 2024 Wiley‐VCH GmbH.)

The osteogenic microenvironment (OME) significantly influences bone repair; however, reproducing its dynamic activation and repair processes remains challenging. In this study, we designed injectable porous microspheres modified with composite peptides to investigate cascade alterations in OME and their underlying mechanisms. Poly l -lactic acid microfluidic microspheres underwent surface modifications through alkaline hydrolysis treatment, involving heterogeneous grafting of bovine serum albumin nanoparticles with stem cell-homing peptides (BNP@SKP) and BMP-2 mimicking peptides (P24), respectively. These modifications well-organized the actions of initial release and subsequent in situ grafting of peptides. Cellular experiments demonstrated varied degrees of chemotactic recruitment and osteogenic differentiation in mesenchymal stem cells. Further biological analysis revealed that BNP@SKP targeted the Ras/Erk axis and upregulated matrix metalloproteinase (MMP)2 and MMP9 expression, thereby enhancing initial chemotaxis and recruitment. In vivo studies validated the establishment of a dynamically regulated OME centered on the microspheres, resulting in increased stem cell recruitment, sequential activation of the differentiation microenvironment, and facilitation of in situ osteogenesis without ectopic ossification. In conclusion, this study successfully fabricated composite peptide-modified microspheres and systematically explored the mechanisms of bone formation through sequential activation of OME via heterogeneous grafting of signaling molecules. This provides theoretical evidence for biomaterials based on microenvironment regulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

As regulators and promotors of joint erosion, pro-inflammatory M1-like macrophages play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Here, we develop a supramolecular self-assembly (PCSN@MTX) of molybdenum (Mo) based polyoxometalate (POM), β-cyclodextrin (β-CD), and methotrexate (MTX), in which the MTX is loaded by host-guest interaction. PCSN@MTX shows inhibition of synovial M1-like macrophages polarization to alleviate RA. PCSN@MTX has demonstrated ultrasound (US) augmented catalytic behavior in consuming ROS and generating oxygen (O 2 ) with accelerated conversion of Mo 5+ to Mo 6+ in the POM. In the collagen-induced arthritis mouse model, after systemical administration, the pH-responsive PCSN@MTX shows enhanced accumulation in the acidic joints by in-situ self-assembly. The host-guest complexation between MTX and β-CD is broken via US, achieving an on-demand burst release of MTX. The released MTX and ROS-scavenging synergistically facilitate the M1-to-M2 macrophage phenotype switching, which effectively alleviates RA disease progress under US irradiation. This study provides a paradigm for RA therapy with a promising US-augmented strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Global aging heightens the risk of oral disorders, among which periodontitis is the major cause of tooth loss in the aging population. The regeneration of damaged periodontal hard tissue is highly challenging due to the existence of the refractory local inflammation. Owing to the potent anti-inflammatory capabilities, regulatory T cells hold great promise in immunotherapies for tissue regeneration. However, the transferred regulatory T cells can alter their phenotypes and functions in local inflammatory milieu, significantly impairing their therapeutic efficacy. Herein, we introduce a novel regulatory T cell-based nanobiohybrid system bearing polyphenol-functionalized rapamycin nanocomplexes. The sustained in situ release of immunosuppressant rapamycin from the cell-attached nanocomplexes maintains the anti-inflammatory phenotype of regulatory T cells in the inflammatory milieu. The synergistic actions of the anti-inflammatory cytokines secreted and the immunosuppressant released guide a pro-resolving polarization of macrophages and enhance osteogenic differentiation of bone marrow-derived stromal cells. The stabilized phenotype of the regulatory T cells dramatically promoted the resolution of periodontal inflammation and the repair of the hard tissue (alveolar bone) in vivo. Overall, these studies highlight a potent regulatory T cell-based nanobiohybrid therapy to treat periodontitis by modulating periodontal immune microenvironment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cell metabolism, as the key driver of inflammation, revascularization and even subsequent tissue regeneration, is controlled by and also conversely influenced by signal transduction. Incorporation of cell metabolism into tissue engineering research holds immense potential for in-situ treatment repair and further understanding of the host-biomaterial cues in body response. In this study, an anti-inflammatory waterborne polyurethane scaffold incorporated with poly-l-lactic acid (PLLA) block was served to repair nerve injuries (LAx-WPU). Lactate was released through the degradation of LAx-WPU scaffolds, and the content increased with the addition of PLLA block over the degradation times. Thenceforth, the production of adenosine triphosphate (ATP) in primary neurons and neuronal axon growth were achieved by taking up lactate through monocarboxylate transporters (MCT2) for energy metabolism under glucose-free environment treated with LAx-WPU degradation solution. After LAx-WPU was implanted to repair brain nerve defects in rats, filamentous neurons elongation, rapid vascularization, and nerve tissue regeneration were realized up to 28 days with the positive expression of microtubule-associated protein (MAP2), β-tubulin (Tuj1), and platelet endothelial cell adhesion molecule (CD31) in the scaffolds. Results highlighted that the LAx-WPU scaffolds up-regulated not only the ATP-ADP-AMP purine metabolism compounds to mainly bridge neuroactive ligand-receptor interaction genes, cAMP pathway genes, and calcium pathway genes for neurocytes but also the ATP-GMP purine metabolism to angiogenesis in Gene Ontology (GO) analysis. Further analysis in reverse showed axonal regeneration is restrained by the inhibition of MCT2, proving LAx-WPU promoted nerve repair depended on lactate for energy. Therefore, LAx-WPU scaffolds construct an expected way to modulate the metabolic microenvironment for inducing nerve regeneration by intrinsic biomaterial metabolism cues without any bioactive factors., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Diabetic wound (DW), notorious for prolonged healing processes due to the unregulated immune response, neuropathy, and persistent infection, poses a significant challenge to clinical management. Current strategies for treating DW primarily focus on alleviating the inflammatory milieu or promoting angiogenesis, while limited attention has been given to modulating the neuro-immune microenvironment. Thus, we present an electrically conductive hydrogel dressing and identify its neurogenesis influence in a nerve injury animal model initially by encouraging the proliferation and migration of Schwann cells. Further, endowed with the synergizing effect of near-infrared responsive release of curcumin and nature-inspired artificial heterogeneous melanin nanoparticles, it can harmonize the immune microenvironment by restoring the macrophage phenotype and scavenging excessive reactive oxygen species. This in-situ formed hydrogel also exhibits mild photothermal therapy antibacterial efficacy. In the infected DW model, this hydrogel effectively supports nerve regeneration and mitigates the immune microenvironment, thereby expediting the healing progress. The versatile hydrogel exhibits significant therapeutic potential for application in DW healing through fine-tuning the neuro-immune microenvironment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Wound infections represent a significant clinical challenge. In this study, a polyphenol (tannic acid, TA)-enhanced borate hydrogel modulating the tissue microenvironment to promote wound healing was designed as an antimicrobial hydrogel. The physical properties of the multiply cross-linked borate hydrogel were analyzed using a combination of techniques, including FT-IR, 1 H NMR, SEM, and rheological analysis. The combination of polyvinyl alcohol (PVA), phenylboronic acid-functionalized chitosan (N-PBACS), and TA resulted in the formation of multi-crosslinked networks (PVA@N-PBACS, TA@PVA, and TA@N-PBACS) that markedly enhanced the hydrogel's mechanical strength, deformability (compression and tensile), and adhesion properties. The multi-crosslinked hydrogels exhibited broad-spectrum antimicrobial activity and antioxidant effects in vitro, as well as excellent biocompatibility and the promotion of cell proliferation, migration and vascularisation behaviours. The in vivo results demonstrated that the hydrogel had enhanced properties. Furthermore, it exhibits good biocompatibility, reactive oxygen species (ROS) scavenging ability, antimicrobial properties, and the ability to modulate immune status. In an in vivo bacterial infection model, the multi-crosslinked hydrogel effectively modulated the wound microenvironment through antimicrobial effects, oxidative stress, ROS levels, and immunity modulation. This study offers a promising solution for improving wound care and provides insight into potential future therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cholestatic liver diseases, accompanied by the hepatic accumulation of bile salts, frequently lead to liver fibrosis, while underlying profibrogenic mechanisms remain incompletely understood. Here, we evaluated the role of extracellular pH (pHe) on bile salt entry and hepatic stellate cell (HSC) activation and proliferation. As modulators of intracellular pH (pHi), various proton pump inhibitors (PPI) were tested for their ability to prevent bile salt entry and HSC activation. Lastly, the PPI pantoprazole was employed in the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-diet model of cholestatic liver fibrosis. We found in vitro, that slightly acidic pHe (7.2-7.3) enhanced bile salt accumulation in HSC and was a prerequisite to bile salt-induced HSC activation. Pantoprazole in the DDC model exhibited antifibrotic effects. We conclude that bile salt-induced activation of HSC may depend on the slightly acidic microenvironment present in the perisinusoidal space and modulation of pHi in HSC may offer a novel pharmacological target in cholestatic disease., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Liver fibrosis is a pathological repair response that occurs after sustained liver damage, and prompt intervention is necessary to prevent liver fibrosis from developing into a potentially life-threatening condition. In long-term liver injury, damaged hepatocytes produce excessive amounts of reactive oxygen species (ROS), which activate hepatic stellate cells (HSCs). This activation leads to excessive accumulation of extracellular matrix proteins in liver tissue. Additionally, liver macrophages contribute to the inflammatory microenvironment in the hepatic fibrotic process, exacerbating liver fibrosis through ROS production and the secretion of pro-inflammatory factors. To address the dysregulation of the hepatic microenvironment associated with liver fibrosis, we developed cerium oxide nanozymes using hyaluronic acid (HA) as a template and decorated them on the surface of liposomes loaded with oleanolic acid (OA). We named this prepared and obtained target-engineered liposome HCOL. The inherent superoxide dismutase (SOD) and catalase (CAT) activities of HCOL enabled it to effectively scavenge ROS in HSCs and alleviate the hypoxic conditions characteristic of fibrotic livers. Furthermore, HCOL reduced the concentrations of ROS in macrophages, promoting a shift in macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. This transition increased the production of the anti-inflammatory cytokine interleukin 10 (IL-10), which contributed to the mitigation of the inflammatory microenvironment. Consequently, this therapeutic approach proves effective in decelerating the advancement of liver fibrosis.

The regeneration of osteoporotic bone defects remains challenging as the critical stem cell function is impaired by inflammatory microenvironment. Synthetic materials that intrinsically direct osteo-differentiation versus self-renewal of recruited stem cell represent a promising alternative strategy for endogenous bone formation. Therefore, a microenvironmentally optimized polyurethane (PU) /n-HA scaffold to enable sustained delivery of gastrodin is engineered to study its effect on the osteogenic fate of stem cells. It exhibited interconnected porous networks and an elevated sequential gastrodin release pattern to match immune-osteo cascade concurrent with progressive degradation of materials. In a critical-sized femur defect model of osteoporotic rat, 5% gastrodin-PU/n-HA potently promoted neo-bone regeneration by facilitating M2 macrophage polarization and CD146 + host stem cell recruitment to defective site. The implantation time-dependently increased the bone marrow mesenchymal stem cell (BMSC) population, and further culture of BMSCs showed a robust ability of proliferation, migration, and mitochondrial resurgence. Of note, some of cell pairs produced one stemness daughter cell while the other committed to osteogenic lineage in an asymmetric cell division (ACD) manner, and a much more compelling ACD response was triggered when 5% gastrodin-PU/n-HA implanted. Further investigation revealed that one-sided concentrated presentation of aPKC and β-catenin in dividing cells effectively induced asymmetric distribution, which polarized aPKC biased the response of the daughter cells to Wnt signal. The asymmetric cell division in skeletal stem cells (SSCs) was mechanically comparable to BMSCs and also governed by distinct aPKC and β-catenin biases. Concomitantly, delayed bone loss adjacent to the implant partly alleviated development of osteoporosis. In conclusion, our findings provide insight into the regulation of macrophage polarization combined with osteogenic commitment of recruited stem cells in an ACD manner, advancing scaffold design strategy for endogenous bone regeneration., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Diabetic wounds are usually entangled in a disorganized and self-perpetuating microenvironment and accompanied by a prolonged delay in tissue repair. Sustained and coordinated microenvironment regulation and tissue regeneration are key to the healing process of diabetic wounds, yet they continue to pose a formidable challenge. Here we report a rational double-layered dressing design based on chitosan and a degradable conjugated polymer polydiacetylene, poly(deca-4,6-diynedioic acid) (PDDA), that can meet this intricate requirement. With an alternating ene-yne backbone, PDDA degrades when reacting with various types of reactive oxygen species (ROS), and more importantly, generates proliferative succinic acid as a major degradant. Inheriting from PDDA, the developed PDDA-chitosan double layer dressing (PCD) can eliminate ROS in the microenvironment of diabetic wounds, alleviate inflammation, and downregulate gene expression of innate immune receptors. PCD degradation also triggers simultaneous release of succinic acid in a sustainable manner, enabling long-term promotion on tissue regeneration. We have validated the biocompatibility and excellent performance of PCD in expediting the wound healing on both diabetic mouse and porcine models, which underscores the significant translational potential of this microenvironment-modulating, growth-promoting wound dressing in diabetic wounds care., Competing Interests: Competing interests The Authors declare no competing interest., (© 2024. The Author(s).)

During intervertebral disc (IVD) degeneration, microenvironmental challenges such as decreasing levels of glucose, oxygen, and pH play crucial roles in cell survival and matrix turnover. Antacids, such as Mg(OH) 2 and CaCO 3 , entrapped in microcapsules are capable of neutralizing acidic microenvironments in a controlled fashion and therefore may offer the potential to improve the acidic niche of the degenerated IVD and enhance cell-based regeneration strategies. The objectives of this work were, first, to develop and characterize antacid microcapsules and assess their neutralization capacity in an acidic microenvironment and, second, to combine antacid microcapsules with cellular microcapsules in a hybrid gel system to investigate their neutralization effect as a potential therapeutic in a disc explant model. To achieve this, we screened five different pH- neutralizing agents (Al(OH) 3 , Mg(OH) 2 , CaCO 3 , and HEPES) in terms of their pH neutralization capacities, with Mg(OH) 2 or CaCO 3 being carried forward for further investigation. Antacid-alginate microcapsules were formed at different concentrations using the electrohydrodynamic spraying process and assessed in terms of size, buffering kinetics, cell compatibility, and cytotoxicity. Finally, the combination of cellular microcapsules and antacid capsules was examined in a bovine disc explant model under physiological degenerative conditions. Overall, CaCO 3 was found to be superior in terms of neutralization capacities, release kinetics, and cellular response. Specifically, CaCO 3 elevated the acidic pH to neutral levels and is estimated to be maintained for several weeks based on Ca 2+ release. Using a disc explant model, it was demonstrated that CaCO 3 microcapsules were capable of increasing the local pH within the core of a hybrid cellular gel system. This work highlights the potential of antacid microcapsules to positively alter the challenging acidic microenvironment conditions typically observed in degenerative disc disease, which may be used in conjunction with cell therapies to augment regeneration., (© 2024 The Author(s). Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Periodontitis suffer from inflammation-induced destruction of periodontal tissues, resulting in the serious loss of alveolar bone. Controlling inflammation and promoting bone regeneration are two crucial aspects for periodontitis-related alveolar bone defect treatment. Herein, we developed a hierarchically structured nanofibrous scaffold with a nano-embossed sheath and a bone morphogenetic protein 2-loaded core to match the periodontitis-specific features that spatiotemporally modulated the osteoimmune environment and promoted periodontal bone regeneration. We investigated the potential of this unique scaffold to treat periodontitis-related alveolar bone defects in vivo and in vitro. The results demonstrated that the hierarchically structured scaffold effectively reduced the inflammatory levels in macrophages and enhanced the osteogenic potential of bone mesenchymal stem cells in an inflammatory microenvironment. Moreover, in vivo experiments revealed that the hierarchically structured scaffold significantly ameliorated inflammation in the periodontium and inhibited alveolar bone resorption. Notably, the hierarchically structured scaffold also exhibited a prolonged effect on promoting alveolar bone regeneration. These findings highlight the significant therapeutic potential of hierarchically structured nanofibrous scaffolds for the treatment of periodontitis, and their promising role in the field of periodontal tissue regeneration. STATEMENT OF SIGNIFICANCE: We present a novel hierarchically structured nanofibrous scaffold of coupling topological and biomolecular signals for precise spatiotemporal modulation of the osteoimmune micro-environment. Specifically, the scaffold was engineered via coaxial electrospinning of the poly(ε-caprolactone) sheath and a BMP-2/polyvinyl alcohol core, followed by surface-directed epitaxial crystallization to generate cyclic nano-lamellar embossment on the sheath. With this unique hierarchical structure, the cyclic nano-lamellar sheath provided a direct nano-topographical cue to alleviate the osteoimmune environment, and the stepwise release of BMP-2 from the core provided a biological cue for bone regeneration. This research underscores the potential of hierarchically structured nanofibrous scaffolds as a promising therapeutic approach for periodontal tissue regeneration and highlights their role in advancing periodontal tissue engineering., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Successful bone regeneration requires close cooperation between bone marrow mesenchymal stem cells (BMSCs) and macrophages, but the low osteogenic differentiation efficiency of stem cells and the excessive inflammatory response of immune cells hinder the development of bone repair. It is necessary to develop a strategy that simultaneously regulates the osteogenic differentiation of BMSCs and the anti-inflammatory polarization of macrophages for accelerating the bone regeneration. Herein, calcium-chlorogenic acid nanoparticles (Ca-CGA NPs) are synthesized by combining the small molecules of chlorogenic acid (CGA) with Ca 2+ . Ca-CGA NPs internalized by cells can be dissolved to release free CGA and Ca 2+ under low pH conditions in lysosomes. In vitro results demonstrate that Ca-CGA NPs can not only enhance the osteogenic differentiation of BMSCs but also promote the phenotype transformation of macrophages from M1 to M2. Furthermore, in vivo experiments confirm that Ca-CGA NPs treatment facilitates the recovery of rat skull defect model through both osteoinduction and immunomodulation. This study develops a new Ca-CGA NPs-based strategy to induce the differentiation of BMSCs into osteoblasts and the polarization of macrophages into M2 phenotype, which is promising for accelerating bone repair., (© 2024 Wiley‐VCH GmbH.)

The pro-inflammatory immune microenvironment in the localized lesion areas and the absence of DNA damage repair mechanisms in endothelial cells serve as essential accelerating factors in the development of atherosclerosis. The lack of targeted therapeutic strategies represents a significant limitation in the efficacy of therapeutic agents for atherosclerosis. In this study, Genetically engineered SNHG12-loaded cerium-macrophage exosomes (Ce-Exo) are designed as atherosclerosis-targeting agents. In vivo studies demonstrated that Ce-Exo exhibited multivalent targeting properties for macrophages, with a 4.1-fold higher atherosclerotic plaque-aggregation ability than that of the control drugs. This suggests that Ce-Exo has a higher homing capacity and deeper penetration into the atherosclerotic plaque. In apolipoprotein E-deficient mice, Ce-Exo found to effectively remodel the immune microenvironment in the lesion area, repair endothelial cell damage, and inhibit the development of atherosclerosis. This study provides a novel approach to the treatment of atherosclerosis and demonstrates the potential of cell-derived drug carriers in biomedicine., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Oral lichen planus (OLP) is an autoimmune disease that significantly impacting patients' life quality. To investigate the clinical efficacy of platelet-rich plasma (PRP) gel coupled with tacrolimus ointment in managing erosive oral lichen planus (EOLP) and its effect on the oral immune environment, 80 EOLP patients were selected from 2021 to 2023 and randomised to two groups in our hospital. Both groups were given tacrolimus ointment, the study group added PRP gel. Comparative analysis of lesion area scores and overall treatment effects, wound pain index, salivary inflammatory factors and CD3+, CD4+, CD8+, CD4+/CD8+ ratio, immunoglobulin M (IgM) Changes, adverse reactions and relapses records. After treatment, compared to the control group, the overall effective rate of the study group was significantly higher, the lesion area and VAS score decreased, inflammatory factors decreased and immune indexes improved (elevated CD3+, CD4+ and CD4+/CD8+ and a decrease in CD8+ and IgM) (P<0.05). Neither of them with serious adverse reactions (P>0.05). The study group's recurrence rate was lower than the control group's (P<0.05). This study demonstrated that PRP gel combined with tacrolimus ointment is superior to tacrolimus ointment alone for the treatment of EOLP and can be further applied to clinical treatment.

The distinctive composition and functions of osteochondral structures result in constrained regeneration. Insufficient healing processes may precipitate the emergence of tissue growth disorders or excessive subchondral bone formation, which can culminate in the deterioration and failure of osteochondral tissue repair. To overcome these limitations, materials designed for osteochondral repair must provide region-specific modulation of the microenvironment and mechanical compatibility. To address these challenges, we propose a method to create continuous hydrogels with distinct structural and functional properties by a precise cross-linking method. We have developed an innovative polyurethane enriched with dimethylglyoxime, facilitating the coordinated loading and precise release of Zn 2+ . This strategy enables the meticulous control of alginate cross-linking, resulting in an elastic gradient hydrogel that closely resembles the osteochondral interface. The SeSe within the hydrogel effectively modulates the inflammatory microenvironment and fosters the M2 polarization of macrophages. The hydrogel's lower layer is designed to rapidly release Zn 2+ , thereby enhancing bone regeneration. The upper layer is intended to prevent bone overgrowth and stimulate chondrogenic differentiation. This dual-layer strategy allows targeted stimuli to each region, promoting the seamless integration of neoosteochondral tissue. Our study demonstrates the potential of this stratified hydrogel in achieving uniform and smooth osteochondral tissue regeneration., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Creating a bone homeostasis microenvironment that balances osteogenesis and immunity is a substantial challenge for bone regeneration. Here, we prepared an immunomodulatory and osteogenic bacterial cellulose scaffold (FOBS) via a facile one-pot approach. The aldehyde groups were generated via selective oxidation of the hydroxyl groups of bacterial cellulose, offering the bonding sites for dopamine through a Schiff base reaction. At the same time, the deposition of Ca 2+ and PO 4 3- was promoted on the aldehyde cellulose scaffold because of the high affinity of the catechol moiety for Ca 2+ . Compared with that of the unmodified scaffold, the hydroxyapatite content of FOBS increased by 47.1 % according to the ICP results. Interestingly, FOBS regulated the immune microenvironment to accelerate the conversion of M1 to M2 macrophages. The expressions of ARG-1 and Dectin-1 (M2) in the FOBS group increased by >100 %. The expression of osteogenic differentiation of BMSCs was also upregulated. In a rat cranial defect model, the BV/TV of FOBS was significantly increased. Further immunohistochemical analysis revealed that an improved immune microenvironment promoted the osteogenic differentiation of stem cells in vivo. This work provides an effective and easy-to-operate strategy for the development of the bone tissue engineering scaffolds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Macrophages play a central role in orchestrating the inflammatory response to implanted biomaterials and are sensitive to changes in the chemical and physical characteristics of the implant. Macrophages respond to biological, chemical, and physical cues by polarizing into pro-inflammatory (M1) or anti-inflammatory (M2) states. We previously showed that rough-hydrophilic titanium (Ti) implants skew macrophage polarization towards an anti-inflammatory phenotype and increase mesenchymal stem cell (MSC) recruitment and bone formation around the implant. In the present study, we aimed to investigate whether the adoptive transfer of macrophages in different polarization states would alter the inflammatory microenvironment and improve biomaterial integration in macrophage-competent and macrophage-ablated mice. We found that ablating macrophages increased the presence of neutrophils, reduced T cells and MSCs, and compromised the healing and biomaterial integration process. These effects could not be rescued with adoptive transfer of naïve or polarized macrophages. Adoptive transfer of M1 macrophages into macrophage-competent mice increased inflammatory cells and inflammatory microenvironment, resulting in decreased bone-to-implant contact. Adoptive transfer of M2 macrophages into macrophage-competent mice reduced the pro-inflammatory environment in the peri‑implant tissue and increased bone-to-implant contact. Taken together, our results show the importance of macrophages in controlling and modulating the inflammatory process in response to implanted biomaterials and suggest they can be used to improve outcomes following biomaterial implantation. STATEMENT OF SIGNIFICANCE: Macrophages are central in orchestrating the inflammatory response to implanted biomaterials and are sensitive to biomaterial chemical and physical characteristics. Our study shows that a deficiency of macrophages results in prolonged inflammation and abolishes bone-biomaterial integration. Adoptive transfer of immunomodulatory macrophages into macrophage-competent mice reduced the inflammatory environment and increased bone-implant contact., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Molecular hydrogen (H 2 ) has antioxidant, anti-inflammatory, and anti-fibrotic effects. In a rat model simulating pulmonary fibrotic changes induced by monocrotaline-induced pulmonary hypertension (MPH), we had previously explored the impact of inhaled H 2 on lung inflammation and blood pressure. In this study, we further focused the biological effects of H 2 on mast cells (MCs) and the parameters of the fibrotic phenotype of the local tissue microenvironment. MPH resulted in a significantly increased number of MCs in both the pneumatic and respiratory parts of the lungs, an increased number of tryptase-positive MCs with increased expression of TGF-β, activated interaction with immunocompetent cells (macrophages and plasma cells) and fibroblasts, and increased MC colocalization with a fibrous component of the extracellular matrix of connective tissue. The alteration in the properties of the MC population occurred together with intensified collagen fibrillogenesis and an increase in the integral volume of collagen and elastic fibers of the extracellular matrix of the pulmonary connective tissue. The exposure of H 2 together with monocrotaline (MCT), despite individual differences between animals, tended to decrease the intrapulmonary MC population and the severity of the fibrotic phenotype of the local tissue microenvironment compared to changes in animals exposed to the MCT effect alone. In addition, the activity of collagen fibrillogenesis associated with MCs and the expression of TGF-β and tryptase in MCs decreased, accompanied by a reduction in the absolute and relative content of reticular and elastic fibers in the lung stroma. Thus, with MCT exposure, inhaled H 2 has antifibrotic effects involving MCs in the lungs of rats. This reveals the unknown development mechanisms of the biological effects of H 2 on the remodeling features of the extracellular matrix under inflammatory background conditions of the tissue microenvironment.

Background: In diabetic wounds, hyperglycemia-induced cytotoxicity and impaired immune microenvironment plasticity directly hinder the wound healing process. Regulation of the hyperglycemic microenvironment and remodeling of the immune microenvironment are crucial., Results: Here, we developed a nanozymatic functionalized regenerative microenvironmental regulator (AHAMA/CS-GOx@Zn-POM) for the effective repair of diabetic wounds. This novel construct integrated an aldehyde and methacrylic anhydride-modified hyaluronic acid hydrogel (AHAMA) and chitosan nanoparticles (CS NPs) encapsulating zinc-based polymetallic oxonate nanozyme (Zn-POM) and glucose oxidase (GOx), facilitating a sustained release of release of both enzymes. The GOx catalyzed glucose to gluconic acid and (H₂O₂), thereby alleviating the effects of the hyperglycemic microenvironment on wound healing. Zn-POM exhibited catalase and superoxide dismutase activities to scavenge reactive oxygen species and H₂O₂, a by-product of glucose degradation. Additionally, Zn-POM induced M1 macrophage reprogramming to the M2 phenotype by inhibiting the MAPK/IL-17 signaling diminishing pro-inflammatory cytokines, and upregulating the expression of anti-inflammatory mediators, thus remodeling the immune microenvironment and enhancing angiogenesis and collagen regeneration within wounds. In a rat diabetic wound model, the application of AHAMA/CS-GOx@Zn-POM enhanced neovascularization and collagen deposition, accelerating the wound healing process., Conclusions: Therefore, the regenerative microenvironment regulator AHAMA/CS-GOx@Zn-POM can achieve the effective conversion of a pathological microenvironment to regenerative microenvironment through integrated control of the hyperglycemic-immune microenvironment, offering a novel strategy for the treatment of diabetic wounds., (© 2024. The Author(s).)

Background: Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy., Objective and Rationale: This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy., Search Methods: A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine)., Outcomes: The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors., Wider Implications: Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field., Registration Number: Not applicable., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Fiber-reinforcement approaches have been used to replace aligned tissues with engineered constructs after injury or surgical resection, strengthening soft biomaterial scaffolds and replicating anisotropic, load-bearing properties. However, most studies focus on the macroscale aspects of these scaffolds, rarely considering the cell-biomaterial interactions that govern remodeling and extracellular matrix organization toward aligned neo-tissues. As initial cell-biomaterial responses within fiber-reinforced microenvironments likely influence the long-term efficacy of repair and regeneration strategies, here we elucidate the roles of spatial orientation, substrate stiffness, and matrix remodeling on early cell-fiber interactions. Bovine mesenchymal stromal cells (MSCs) were cultured in soft fibrin gels reinforced with a stiff 100 µm polyglycolide-co-caprolactone fiber. Gel stiffness and remodeling capacity were modulated by fibrinogen concentration and aprotinin treatment, respectively. MSCs were imaged at 3 days and evaluated for morphology, mechanoresponsiveness (nuclear Yes-associated protein [YAP] localization), and spatial features including distance and angle deviation from fiber. Within these constructs, morphological conformity decreased as a function of distance from fiber. However, these correlations were weak ( R 2 = 0.01043 for conformity and R 2 = 0.05542 for nuclear YAP localization), illustrating cellular heterogeneity within fiber-enforced microenvironments. To better assess cell-fiber interactions, we applied machine-learning strategies to our heterogeneous dataset of cell-shape and mechanoresponsive parameters. Principal component analysis (PCA) was used to project 23 input parameters (not including distance) onto 5 principal components (PCs), followed by agglomerative hierarchical clustering to classify cells into 3 groups. These clusters exhibited distinct levels of morpho-mechanoresponse (combination of morphological conformity and YAP signaling) and were classified as high response (HR), medium response (MR), and low response (LR) clusters. Cluster distribution varied spatially, with most cells (61%) closest to the fiber (0-75 µm) belonging to the HR cluster, and most cells (55%) furthest from the fiber (225-300 µm) belonging to the LR cluster. Modulation of gel stiffness and fibrin remodeling showed differential effects for HR cells, with stiffness influencing the level of mechanoresponse and remodeling capacity influencing the location of responding cells. Together, these novel findings demonstrate early trends in cellular patterning of the fiber-reinforced microenvironment, showing how spatial orientation, substrate biophysical properties, and matrix remodeling may guide the amplitude and localization of cellular mechanoresponses. These trends may guide approaches to optimize the design of microscale scaffold architecture and substrate properties for enhancing organized tissue assembly at the macroscale.

Background: In diabetic wounds, M2 polarization of macrophages regulates the transition from an inflammatory phase to a proliferative phase. Prior investigations have demonstrated the potential of deferoxamine (DFO) in creating a localized hypoxic microenvironment, which could stimulate angiogenesis by promoting vascular endothelial growth factor (VEGF) secretion in diabetic wound healing. Nevertheless, there is still no clear information on whether this chemically induced hypoxic microenvironment modulates macrophage polarization to promote diabetic wound healing., Methods: The 18 diabetic mice were randomly divided into three groups: a control group (n = 6), a 100µM DFO group (n = 6), and a 200µM DFO group (n = 6). Subsequently, a full-thickness wound with a diameter of 1.00 cm was created on the dorsal region of the diabetic mice. Observe wound closure regularly during treatment. At the end of the observation, tissue specimens were collected for a series of experiments and analyses, including hematoxylin and eosin (H&E), Masson, immunofluorescent, and immunohistochemical staining. The role and mechanism of DFO in regulating macrophage polarization were studied using RAW264.7 cells., Results: In comparison to the control group, the administration of DFO notably facilitates wound healing in diabetic mice. In diabetic wounds, DFO increases blood supply by upregulating VEGF, which promotes angiogenesis. Additionally, The expression of HSP70 and CD206 were also upregulated by DFO in both vivo and in vitro, while iNOS expression was downregulated. Additionally, knk437 inhibited the expression of HSP70 in RAW264.7 cells, resulting in a reduction of M2 polarization and an increase in M1 polarization., Conclusion: The induction of a hypoxic microenvironment by DFO has been found to exert a substantial influence on the process of diabetic wound healing. DFO treatment enhances the capacity of diabetic wounds to stimulate angiogenesis and modulate macrophage polarization that may be associated with HSP70 expression, thereby expediting the transition of these wounds from an inflammatory to a proliferative state., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The complete structure-functional repair of volumetric muscle loss (VML) remains a giant challenge and biomedical hydrogels to remodel microenvironment and enhance neurogenesis have appeared to be a promising direction. However, the current hydrogels for VML repair hardly achieve these two goals simultaneously due to their insufficient functionality and the challenge in high-cost of bioactive factors. In this study, a facile strategy using Nb 2 C MXene-functionalized hydrogel (OPTN) as a bioactive scaffold is proposed to promote VML repair with skeletal muscle regeneration and functional restoration. In vitro experiments show that OPTN scaffold can effectively scavenge reactive oxygen species (ROS), guide macrophages polarization toward M2 phenotype, and resist bacterial infection, providing a favorable microenvironment for myoblasts proliferation as well as the endothelial cells proliferation, migration, and tube formation. More importantly, OPTN scaffold with electroactive feature remarkably boosts myoblasts differentiation and mesenchymal stem cells neural differentiation. Animal experiments further confirm that OPTN scaffold can achieve a prominent structure-functional VML repair by attenuating ROS levels, alleviating inflammation, reducing fibrosis, and facilitating angiogenesis, newborn myotube formation, and neurogenesis. Collectively, this study provides a highly promising and effective strategy for the structure-functional VML repair through designing bioactive multifunctional hydrogel with microenvironment remodeling and enhanced neurogenesis., (© 2024 Wiley‐VCH GmbH.)

The protein epidermal growth factor (EGF), which plays a crucial role in promoting cell proliferation and survival, has recently demonstrated potential in reducing inflammation. In this study, we examined the impact of EGF on the anti-inflammatory and anti-proliferative properties of pterygium, a prevalent hypervascular proliferative disease affecting the ocular surface. In surgically excised tissues, markers for fibrotic and inflammatory signals, including VIM, ACTA2, FAP, MMP2, VCAM1, ICAM1, CD86, IL6, and IL1B were upregulated in the pterygium body stroma compared to the normal conjunctival stroma. EGF exerted anti-inflammatory and anti-vasculogenic effects on pterygial fibroblasts when co-cultured with M1 macrophages. Moreover, exosomes derived from EGF-preconditioned M1 macrophages suppressed the heightened inflammatory and vasculogenic signals in pterygial fibroblasts induced by exosomes from M1 macrophages. Paradoxically, the proliferation of pterygial fibroblasts was inhibited by EGF in the in vitro microenvironment with M1 macrophages, despite EGF being known as a growth factor. EGF-preconditioning of M1 macrophages rescued the increased proliferation of pterygial fibroblasts induced by exosomes from M1 macrophages. In conclusion, our findings demonstrate that EGF effectively mitigates inflammation and proliferation in pterygial fibroblasts within a microenvironment containing M1 macrophages., (© 2024. The Author(s).)

Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4 + T and CD8 + T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4 + /CD8 + T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro. Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ischemic stroke, a common neurological disorder caused by impaired blood supply to the brain, presents a therapeutic challenge. Conventional treatments like thrombolysis and neuroprotection drugs lack ideal drug delivery systems, limiting their effectiveness. Selectively delivering therapies to the ischemic cerebral tissue holds great potential for preventing and/or treating ischemia-related pathological symptoms. The unique pathological microenvironment of the brain after ischemic stroke, characterized by hypoxia, acidity, and inflammation, offers new possibilities for targeted drug delivery. Pathological microenvironment-responsive nanosystems, extensively investigated in tumors with hypoxia-responsive systems as an example, could also respond to the ischemic cerebral microenvironment and achieve brain-targeted drug delivery and release. These emerging nanosystems are gaining traction for ischemic stroke treatment. In this review, we expound on the cerebral pathological microenvironment and clinical treatment strategies of ischemic stroke, highlight various stimulus-responsive materials employed in constructing ischemic stroke microenvironment-responsive nano delivery systems, and discuss the application of these microenvironment-responsive nanosystems in microenvironment regulation for ischemic stroke treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Tissue defect is one of the significant challenges encountered in clinical practice. Nanomaterials, including nanoparticles, nanofibers, and metal-organic frameworks, have demonstrated an extensive potential in tissue regeneration, offering a promising avenue for future clinical applications. Nonetheless, the intricate landscape of the inflammatory tissue microenvironment has engendered challenges to the efficacy of nanomaterial-based therapies. This quandary has spurred researchers to pivot towards advanced nanotechnological remedies for overcoming these therapeutic constraints. Among these solutions, microenvironment-sensitive nanozymes have emerged as a compelling instrument with the capacity to reshape the tissue microenvironment and enhance the intricate process of tissue regeneration. In this review, we summarize the microenvironmental characteristics of damaged tissues, offer insights into the rationale guiding the design and engineering of microenvironment-sensitive nanozymes, and explore the underlying mechanisms that underpin these nanozymes' responsiveness. This analysis includes their roles in orchestrating cellular signaling, modulating immune responses, and promoting the delicate process of tissue remodeling. Furthermore, we discuss the diverse applications of microenvironment-sensitive nanozymes in tissue regeneration, including bone, soft tissue, and cartilage regeneration. Finally, we shed our sights on envisioning the forthcoming milestones in this field, prospecting a future where microenvironment-sensitive nanozymes contribute significantly to the development of tissue regeneration and improved clinical outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)