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Biomimetic Nanozyme-Decorated Hydrogels with H2O2-Activated Oxygenation for Modulating Immune Microenvironment in Diabetic Wound
Abstract
Diabetic foot ulcers (DFUs) remain a devastating threat to human health. While hydrogels are promising systems for DFU-based wound management, their effectiveness is often hindered by the immune response and hostile wound microenvironment associated with the uncontrollable accumulation of reactive oxygen species and hypoxia. Here, we develop a therapeutic wound dressing using a biomimetic hydrogel system with the decoration of catalase-mimic nanozyme, namely, MnCoO@PDA/CPH. The hydrogel can be designed to match the mechanical and electrical cues of skins simultaneously with H2O2-activated oxygenation ability. As a proof of concept, DFU-based rat models are created to validate the therapeutic efficacy of the MnCoO@PDA/CPH hydrogel in vivo. The results indicate that the developed hydrogel can promote DFU healing and improve the quality of the healed wound as featured by alleviated proinflammatory, increased re-epithelialization, highly ordered collagen deposition, and functional blood vessel growth.
... The inclusion of AuPt@melanin nanoparticles notably augmented the antioxidant activity of the GHM3 hydrogel compared to the GHM1 hydrogel lacking AuPt@ melanin, indicating the enhancement in scavenging capabilities for ROS. Zhao et al. 137 incorporated polydopaminemodified MnCoO nanoparticles into hydrogel to harness their exceptional ROS-scavenging capabilities ( Figure 5(d)), expediting the healing process of diabetic wounds. To summarize, ROS-scavenging hydrogels exhibit the potential to alleviate oxidative stress, accelerate regeneration, and synergize with additional therapeutic agents or molecules. ...
... Copyright 2023, American Chemical Society, and (d) MnCoO@PDA/CPH hydrogel with high ROS scavenging capacity in vitro. Reproduced with permission.137 Copyright 2023, American Chemical Society. ...
The rising prevalence of diabetes has underscored concerns surrounding diabetic wounds and their potential to induce disability. The intricate healing mechanisms of diabetic wounds are multifaceted, influenced by ambient microenvironment, including prolonged hyperglycemia, severe infection, inflammation, elevated levels of reactive oxygen species (ROS), ischemia, impaired vascularization, and altered wound physicochemical properties. In recent years, hydrogels have emerged as promising candidates for diabetic wound treatment owing to their exceptional biocompatibility and resemblance to the extracellular matrix (ECM) through a three-dimensional (3D) porous network. This review will first summarize the microenvironment alterations occurring in the diabetic wounds, aiming to provide a comprehensive understanding of its pathogenesis, then a comprehensive classification of recently developed hydrogels will be presented, encompassing properties such as hypoglycemic effects, anti-inflammatory capabilities, antibacterial attributes, ROS scavenging abilities, promotion of angiogenesis, pH responsiveness, and more. The primary objective is to offer a valuable reference for repairing diabetic wounds based on their unique microenvironment. Moreover, this paper outlines potential avenues for future advancements in hydrogel dressings to facilitate and expedite the healing process of diabetic wounds.
... Due to excessive in ammation, ischaemia, and hypoxia in DFUs, the wound immune microenvironment undergoes signi cant alterations, leading to an imbalance in the regulation of immune cells and cytokines during DFU wound healing [32]. The analysis of immune in ltration revealed large differences in the presence of CD8 + T cells, DCs, HLA, MHC class I T helper cells, Th2 cells, and TILs between patients with DFU and controls. ...
Background
Diabetic foot ulcer (DFU) is a prevalent complication associated with diabetes that is characterised by high morbidity, high disability and high mortality and involves chronic inflammation and infiltration of multiple immune cells. However, the molecular mechanisms underlying DFU remain unclear. Here, we aimed to identify the critical signatures in nonhealing DFUs using single-cell RNA sequencing and transcriptomic analysis.
Methods
The GSE165816, GSE134431, and GSE143735 datasets were downloaded from the GEO database. First, we preliminarily processed and screened the datasets, removed low-quality data and identified the cell subsets. Each cell subtype was annotated, and the predominant cell types contributing to the disease were analysed. Based on this information, a prediction model was constructed with the training set GSE134431 and testing set GSE143735. Key genes were identified using the LASSO regression algorithm, followed by verification of model accuracy and stability. Additionally, we investigated the molecular mechanisms and changes in signalling pathways associated with this disease using immunoinfiltration analysis, GSEA, and GSVA.
Results
Through scRNA-seq analysis, we identified 12 distinct cell clusters and determined that the basalKera cell type was important in disease development. A prediction model with high accuracy and stability was constructed incorporating five key genes (TXN, PHLDA2, RPLP1, MT1G, and SDC4). Immune cell infiltration analysis, GSEA, and GSVA revealed alterations in immune cells and signalling pathways throughout disease progression, primarily involving CD8⁺ T cells, T helper cells, the hypoxia-inducible factor signalling pathway, and the interleukin-17 signalling pathway.
Conclusions
Our study identified six key genes, namely, TXN, PHLDA2, RPLP1, MT1G, and SDC4, which are significantly associated with the development of nonhealing DFU and play a crucial role in immune cell infiltration. The identified genes have the potential to serve as new prevention and treatment strategies for DFU.
... Fortunately, nanotechnology presents inherent advantages such as proficient drug delivery and controlled release mechanisms that hold the potential to effectively address the aforementioned limitations (11)(12)(13)(14). Moreover, a particularly promising development emerges: the encapsulation of nanoparticles within cellular membranes has witnessed significant progress, imparting the nanoparticles with an inherent capability for active targeting. ...
Osteoporosis, characterized by a reduction in bone mineral density, represents a prevalent skeletal disorder with substantial global health implications. Conventional therapeutic strategies, exemplified by bisphosphonates and hormone replacement regimens, though...
... For example, Zhao et al. developed a therapeutic wound dressing, namely, MnCoO@PDA/CPH, utilizing a biomimetic hydrogel system and modified hydrogen peroxidemimicking nanozymes. The hydrogel is engineered to simultaneously match the mechanical and electrical signals of the skin while possessing oxidative capability activated by H 2 O 2 34 . Wu et al. prepared a versatile dynamic Schiff base and borate ester cross-linked glycopeptide hydrogel that could continuously generate oxygen, promote M2 polarization of macrophages, and eliminate reactive oxygen and nitrogen species 35 . ...
Chronic diabetic wounds are at lifelong risk of developing diabetic foot ulcers owing to severe hypoxia, excessive reactive oxygen species (ROS), a complex inflammatory microenvironment, and the potential for bacterial infection. Here we develop a programmed treatment strategy employing live Haematococcus (HEA). By modulating light intensity, HEA can be programmed to perform a variety of functions, such as antibacterial activity, oxygen supply, ROS scavenging, and immune regulation, suggesting its potential for use in programmed therapy. Under high light intensity (658 nm, 0.5 W/cm²), green HEA (GHEA) with efficient photothermal conversion mediate wound surface disinfection. By decreasing the light intensity (658 nm, 0.1 W/cm²), the photosynthetic system of GHEA can continuously produce oxygen, effectively resolving the problems of hypoxia and promoting vascular regeneration. Continuous light irradiation induces astaxanthin (AST) accumulation in HEA cells, resulting in a gradual transformation from a green to red hue (RHEA). RHEA effectively scavenges excess ROS, enhances the expression of intracellular antioxidant enzymes, and directs polarization to M2 macrophages by secreting AST vesicles via exosomes. The living HEA hydrogel can sterilize and enhance cell proliferation and migration and promote neoangiogenesis, which could improve infected diabetic wound healing in female mice.
The delayed healing of infected wounds can be attributed to the increased production of reactive oxygen species (ROS) and consequent damages to vascellum and tissue, resulting in a hypoxic wound environment that further exacerbates inflammation. Current clinical treatments including hyperbaric oxygen therapy and antibiotic treatment fail to provide sustained oxygenation and drug‐free resistance to infection. To propose a dynamic oxygen regulation strategy, this study develops a composite hydrogel with ROS‐scavenging system and oxygen‐releasing microspheres in the wound dressing. The hydrogel itself reduces cellular damage by removing ROS derived from immune cells. Simultaneously, the sustained release of oxygen from microspheres improves cell survival and migration in hypoxic environments, promoting angiogenesis and collagen regeneration. The combination of ROS scavenging and oxygenation enables the wound dressing to achieve drug‐free anti‐infection through activating immune modulation, inhibiting the secretion of pro‐inflammatory cytokines interleukin‐6, and promoting tissue regeneration in both acute and infected wounds of rat skins. Thus, the composite hydrogel dressing proposed in this work shows great potential for dynamic redox regulation of infected wounds and accelerates wound healing without drugs.
Skin pathological fibrosis conditions, such as hypertrophic scars (HS) and keloids, where the scar tissue is raised and extends beyond the original wound boundary, are aesthetically unappealing and sometimes painful or itchy, significantly impacting the life quality of patients. In this review, the advances of nanobiomaterials in treating skin pathological fibrosis are summarized and discussed. The focus is on the therapeutic approaches to cellular and molecular targets of HS, highlighting the potential of nanotechnology in scar management. The biofunctional nanomaterials can modulate inflammation, regulate angiogenesis, and promote fibroblast apoptosis. The nanotechnology‐based drug delivery systems such as liposomes, ethosomes, and dendritic macromolecules can improve the solubility, stability, and efficacy of drugs, and enhance precise delivery, resulting in better outcomes in HS therapy. Integrating nanomaterials or nanostructures into hydrogels, nanofibers, and microneedles can enhance the biological functionality and maximize the therapeutic effect of nanoparticles (NPs) at the wound site. The important potential of nanotechnology‐based scar treatment should be further explored to overcome the current challenges and promote its application in clinical practice.
Efficiently removing excess reactive oxygen species (ROS) generated by various factors on the ocular surface is a promising strategy for preventing the development of dry eye disease (DED). The currently available eye drops for DED treatment are palliative, short-lived and frequently administered due to the short precorneal residence time. Here, we developed nanozyme-based eye drops for DED by exploiting borate-mediated dynamic covalent complexation between n-FeZIF-8 nanozymes (n-Z(Fe)) and poly(vinyl alcohol) (PVA) to overcome these problems. The resultant formulation (PBnZ), which has dual-ROS scavenging abilities and prolonged corneal retention can effectively reduce oxidative stress, thereby providing an excellent preventive effect to alleviate DED. In vitro and in vivo experiments revealed that PBnZ could eliminate excess ROS through both its multienzyme-like activity and the ROS-scavenging activity of borate bonds. The positively charged nanozyme-based eye drops displayed a longer precorneal residence time due to physical adhesion and the dynamic borate bonds between phenyboronic acid and PVA or o-diol with mucin. The in vivo results showed that eye drops could effectively alleviate DED. These dual-function PBnZ nanozyme-based eye drops can provide insights into the development of novel treatment strategies for DED and other ROS-mediated inflammatory diseases and a rationale for the application of nanomaterials in clinical settings.
Graphical Abstract
Chronic non-healing wounds are a common consequence of skin ulceration in diabetic patients, with severe cases such as diabetic foot even leading to amputations. The interplay between pathological factors like hypoxia-ischemia, chronic inflammation, bacterial infection, impaired angiogenesis, and accumulation of advanced glycosylation end products (AGEs), resulting from the dysregulation of the immune microenvironment caused by hyperglycemia, establishes an unending cycle that hampers wound healing. However, there remains a dearth of sufficient and effective approaches to break this vicious cycle within the complex immune microenvironment. Consequently, numerous scholars have directed their research efforts towards addressing chronic diabetic wound repair. In recent years, gases including Oxygen (O2), Nitric oxide (NO), Hydrogen (H2), Hydrogen sulfide (H2S), Ozone (O3), Carbon monoxide (CO) and Nitrous oxide (N2O), along with gas-releasing materials associated with them have emerged as promising therapeutic solutions due to their ability to regulate angiogenesis, intracellular oxygenation levels, exhibit antibacterial and anti-inflammatory effects while effectively minimizing drug residue-induced damage and circumventing drug resistance issues. In this review, we discuss the latest advances in the mechanisms of action and treatment of these gases and related gas-releasing materials in diabetic wound repair. We hope that this review can provide different ideas for the future design and application of gas therapy for chronic diabetic wounds.
Diabetic foot ulcers (DFUs), a serious and increasingly common chronic issue among diabetics, often do not respond well to generalized treatment strategies. Hypoxia and the overexpression of reactive oxygen species (ROS), resulting in inflammatory dysregulation and subsequent imbalance in macrophage phenotypes, are critical factors contributing to the prolonged non‐healing of DFU wounds. These two issues often interact in a continuous, problematic cycle. Presently, there is a lack of comprehensive strategies aimed at addressing both of these factors simultaneously to interrupt this detrimental cycle. Herein, an immunomodulatory hydrogel (PHG2) is developed for reshaping the hostile DFU microenvironment. The engineered PHG2 not only removes excess internally‐produced ROS but also generates O2, with its efficiency further boosted by local hyperthermia (42.5 °C) activated by near‐infrared light. Through both in vitro and in vivo studies, along with transcriptomic assessment, it is confirmed that PHG2 disrupts the detrimental feedback loop between ROS and inflammation while also lowering the M1/M2 macrophage ratio. Such discoveries contribute to a significant enhancement in the healing process of injuries that undergo a gradual increase in movement, covering wounds from the back, mouth, to the foot. Ultimately, this method provides an easy, safe, and highly effective solution for treating DFUs.
The regeneration of hypoxia‐impaired chronic tissue defects has long been challenging, mainly due to the inefficiency of oxygenation and the limited biological activity of existing oxygen delivery systems in regulating dynamic tissue regeneration process. Herein, a novel polyphenol‐copper coordination strategy to fabricate bioactive superoxide dismutase‐catalase self‐cascade nanozymes (SalB‐CuNCs) is reported, which can serve as an in situ oxygenator and induce angiogenesis simultaneously. The copper‐phenolic hydroxyl coordination structure in SalB‐CuNCs plays a critical role in promoting the enzyme‐like cascade reaction via catechol‐mediated Cu valence state transition and substrate capture mechanism. Furthermore, after incorporating SalB‐CuNCs into a Schiff base hydrogel (COC@SalB‐Cu), the resulting system exhibits outstanding antioxidant and robust oxygenation effect in mitigating the hypoxic microenvironment. Benefiting from the intrinsic angiogenic activity of SalB and copper, COC@SalB‐Cu hydrogel can induce a more complete tube formation by up‐regulating the expression level of vascular endothelial growth factor (VEGF), platelet‐endothelial cell adhesion molecule‐1 (CD31), and endothelial nitric oxide synthase (eNOS). In vivo experiments further demonstrate that the COC@SalB‐Cu hydrogel can significantly restore the oxygen and blood supply, leading to fast tissue regeneration. The present strategy holds enormous promise for the treatment of hypoxia‐related chronic tissue defects and vascular injury in the field of regenerative medicine.
Developing novel antibacterial dressing protecting skin injuries from infection is essential for wound healing. In this study, sericin, a bio-waste produced during the degumming of silk cocoons, is utilized to exfoliate MoS2 layers and improve the dispersity and stability of MoS2 nanosheets (MoS2-NSs). Moreover, owing to its ability to promote oxygen permeability and cell growth and its good biocompatibility, MoS2-NS/Sericin maintains its photothermal property under an 808 nm light source for a strong antibacterial activity as well as improves the fibroblast migration, which accelerates wound healing. Furthermore, the in vitro experiments indicates that MoS2-NS/Sericin can also scavenge reactive oxygen species (ROS) at an inflammatory stage of wound healing and transform classical activated macrophages (M1-type) into alternatively activated macrophages (M2-type), which is beneficial for wound recovery. Based on these results observed in vitro, full-thickness skin wound experiments are conducted on rats, and the corresponding results show that MoS2/Sericin under 808 nm irradiation exhibits the best performance in promoting wound healing. Overall, MoS2-NS/Sericin exhibits a high potential for bacteria-infected wound healing.
Chronic diabetic wounds persist as a healthcare challenge and therefore require the use of innovative therapeutic approaches. Among emerging solutions, hydrogels stand out as a promising avenue for diabetic wound healing due to their unique properties and versatile applications, capable of addressing the complex and challenging microenvironment that characterizes such wounds. In this work, through a detailed analysis of relevant experimental studies, we highlight the multifunctionality of hydrogels, namely their ability to promote tissue attachment, prevent scarring, fight infection, attenuate inflammation, facilitate electrical signaling, control bleeding, repair damage autonomously, and exhibit responses tailored to specific wound characteristics. The collective findings from these studies emphasize the promising attributes of hydrogels in addressing diabetic wound healing challenges. By elucidating these crucial insights, this work seeks to lay the groundwork both for academics and industries for the development and implementation of effective hydrogel-based strategies that can significantly improve diabetic wound healing outcomes, offering new hope for patients suffering from chronic diabetic wounds.
Delayed wound healing caused by excessive reactive oxygen species (ROS) remains a considerable challenge. In recent years, metal oxide nanozymes have gained significant attention in biomedical research. However, a comprehensive investigation of Co3O4 based nanozymes for enhancing wound healing and tissue regeneration is lacking. This study focuses on developing a facile synthesis method to produce high-stability and cost-effective Co3O4 nanoflakes (NFs) with promising catalase (CAT)-like activity to regulate the oxidative microenvironment and accelerate wound healing. The closely arranged Co3O4 nanoparticles (NPs) within the NFs structure result in a significantly larger surface area, thereby amplifying the enzymatic activity compared to commercially available Co3O4 NPs. Under physiological conditions, it was observed that Co3O4 NFs efficiently break down hydrogen peroxide (H2O2) without generating harmful radicals (·OH). Moreover, they exhibit excellent compatibility with various cells involved in wound healing, promoting fibroblast growth and protecting cells from oxidative stress. In a rat model, Co3O4 NFs facilitate both the hemostatic and proliferative phases of wound healing, consequently accelerating the process. Overall, the promising results of Co3O4 NFs highlight their potential in promoting wound healing and tissue regeneration.
Chronic wounds are a major health challenge that require new treatment strategies. Hydrogels are promising drug delivery systems for chronic wound healing because of their biocompatibility, hydration, and flexibility. However, conventional hydrogels cannot adapt to the dynamic and complex wound environment, which involves low pH, high levels of reactive oxygen species, and specific enzyme expression. Therefore, smart responsive hydrogels that can sense and respond to these stimuli are needed. Crucially, smart responsive hydrogels can modulate drug release and eliminate pathological factors by changing their properties or structures in response to internal or external stimuli, such as pH, enzymes, light, and electricity. These stimuli can also be used to trigger antibacterial responses, angiogenesis, and cell proliferation to enhance wound healing. In this review, we introduce the synthesis and principles of smart responsive hydrogels, describe their design and applications for chronic wound healing, and discuss their future development directions. We hope that this review will inspire the development of smart responsive hydrogels for chronic wound healing.
Multi‐nanozymes are widely applied in disease treatment, biosensing, and other fields. However, most current multi‐nanozyme systems exhibit only moderate activity since reaction microenvironments of different nanozyme are often distinct or even incompatible. Conventional assemble strategies are inapplicable for designing multi‐nanozymes consisting of incompatible nanozymes. Herein, a versatile fiber‐based compartmentalization strategy is developed to construct multi‐nanozyme system capable of simultaneously performing incompatible reactions. In this system, the incompatible nanozymes are spatially distributed in distinct compartmentalized fibers, where different microenvironments can be tailored by controlling the doping reagent, endowing each nanozymes with the preferential microenvironments to exhibit their highest activity. As a proof of concept, pH‐incompatible peroxidase‐like and catalase‐like catalytic reactions are tested to verify the feasibility of this strategy. By doping with benzoic acid in the desired location, the two pH‐incompatible nanozymes can work simultaneously without interference. Further, it is demonstrated that the oxygen supply and antimicrobial power of the integrated platform can be applied for accelerating diabetic wound healing. It is hoped that this work provides a way to integrate incompatible nanozyme and broadens the application potential of multi‐nanozymes.
Stem cell-based therapy has drawn attention for enhancing the osseointegration efficiency after joint replacement in the rheumatoid arthritis (RA). However, therapeutic efficacy of this approach is threatened by the accumulated reactive oxygen species (ROS) and poor oxygen supply. Herein, we develop a nanozyme-reinforced hydrogel for reshaping the hostile RA microenvironment and improving prosthetic interface osseointegration. The engineered hydrogel not only scavenges endogenously over-expressed ROS, but also synergistically produces dissolved oxygen. Such performance enables the hydrogel to be utilized as an injectable delivery vehicle of bone marrow-derived mesenchymal stem cells (BMSCs) to protect implanted cells from ROS and hypoxia-mediated death and osteogenic limitation. This nanozyme-reinforced hydrogel encapsulated with BMSCs can alleviate the symptoms of RA, including suppression of local inflammatory cytokines and improvement of osseointegration. This work provides a strategy for solving the long-lasting challenge of stem cell transplantation and revolutionizes conventional intervention methods for improving prosthetic interface osseointegration in RA.
The treatment of difficult-to-heal wounds remains a substantial clinical challenge due to deteriorative tissue microenvironment including the loss of extracellular matrix (ECM), excessive inflammation, impaired angiogenesis, and bacterial infection. Inspired by the chemical components, fibrous structure, and biological function of natural ECM, antibacterial and tissue environment–responsive glycopeptide hybrid hydrogel was developed for chronic wound healing. The hydrogel can facilitate the cell proliferation and macrophage polarization to M2 phenotype, and show potent antibacterial efficacy against both Gram-negative and Gram-positive bacteria. Significantly, the glycopeptide hydrogel accelerated the reconstruction of methicillin-resistant Staphylococcus aureus (MRSA)–infected full-thickness diabetic and scalding skin by orchestrating a pro-regenerative response indicated by abundant M2-type macrophages, attenuated inflammation, and promoted angiogenesis. Collectively, ECM-mimetic and immunomodulatory glycopeptide hydrogel is a promising multifunctional dressing to reshape the damaged tissue environment without additional drugs, exogenous cytokines, or cells, providing an effective strategy for the repair and regeneration of chronic cutaneous wounds.
The management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial–temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases.
Graphical Abstract
The regeneration of diabetic bone defects remains challenging as the innate healing process is impaired by glucose fluctuation (GF), reactive oxygen species (ROS) and over-expression of proteinases (such as matrix metalloproteinases, MMPs). A “diagnostic” and therapeutic dual logic-based hydrogel for diabetic bone regeneration is therefore developed through the design of a double-network hydrogel consisting of phenyboronic acid-crosslinked polyvinyl alcohol and gelatin colloids. It exhibited a “diagnostic“ logic to interpret pathological cues (GF, ROS, MMPs) and determine when to release drug in a diabetic microenvironment and a therapeutic logic to program different cargo release to match immune-osteo cascade for better tissue regeneration. The hydrogel was also shown to be mechanically adaptable to the local complexity at the bone defect. Furthermore, the underlying therapeutic mechanism was elucidated whereby the logic-based cargo release enabled the regulation of macrophage polarization by remodeling the mitochondria-related antioxidative system, resulting in enhanced osteogenesis in diabetic bone defects. In conclusion, our study provides critical insight into the design and biological mechanism of dual logic-based tissue engineering strategies for diabetic bone regeneration.
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CD8 T cell–mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells¹. How autoimmune T cell populations arise and are sustained and the molecular programs defining the autoimmune T cell state are unknown. In Type 1 diabetes (T1D), beta cell–specific CD8 T cells destroy insulin-producing beta cells. We followed the fate of beta cell–specific CD8 T cells in non-obese diabetic mice throughout the course of T1D. We identified a stem-like autoimmune progenitor (AP) population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators (AM). pLN AM migrate to the pancreas, where they differentiate further and destroy beta cells. While transplantation of as few as 20 AP induced T1D, as many as 100,000 pancreatic AM failed to do so. Pancreatic AM are short-lived and stem-like AP must continuously seed the pancreas to sustain beta cell destruction. Single cell RNA-sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from AP to AM. Strategies aimed at targeting the stem-like AP pool could emerge as novel and powerful immunotherapeutic interventions for T1D.
Anti-adhesion barriers such as films and hydrogels used to wrap repaired tendons are important for preventing the formation of adhesion tissue after tendon surgery. However, sliding of the tendon can compress the adjacent hydrogel barrier and cause it to rupture, which may then lead to unexpected inflammation. Here, a self-healing and deformable hyaluronic acid (HA) hydrogel was constructed as a peritendinous anti-adhesion barrier. Matrix metalloproteinase-2 (MMP-2)-degradable gelatin-methacryloyl (GelMA) microspheres (MSs) encapsulated with Smad3-siRNA nanoparticles were entrapped within the HA hydrogel to inhibit fibroblast proliferation and prevent peritendinous adhesion. Silencing effect of Smad3-siRNA nanoparticles was around 75% towards targeted gene. The mean adhesion scores of composite barrier group were 1.67±0.51 and 2.17±0.75 by macroscopic and histological evaluation, respectively. Furthermore, GelMA MSs were responsively degraded by upregulation of MMP-2, achieving on-demand release of siRNA nanoparticles to inhibit the formation of adhesion tissue. The proposed self-healing hydrogel anti-adhesion barrier with MMP-2-responsive drug release behavior is highly effective for decreasing inflammation and inhibiting tendon adhesion. Therefore, this research provides a new strategy for the development of safe and effective anti-adhesion barriers.
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Current treatments for diabetic ulcers (DUs) remain unsatisfactory due to the risk of bacterial infection and impaired angiogenesis during the healing process. The increased degradation of polyubiquitinated hypoxia‐inducible factor‐1α (HIF‐1α) compromises wound healing efficacy. Therefore, the maintenance of HIF‐1α protein stability might help treat DU. Nitric oxide (NO) is an intrinsic biological messenger that functions as a ubiquitination flow repressor and antibacterial agent; however, its clinical application in DU treatment is hindered by the difficulty in controlling NO release. Here, an intelligent near‐infrared (NIR)‐triggered NO nanogenerator (SNP@MOF‐UCNP@ssPDA‐Cy7/IR786s, abbreviated as SNP@UCM) is presented. SNP@UCM represses ubiquitination‐mediated proteasomal degradation of HIF‐1α by inhibiting its interaction with E3 ubiquitin ligases under NIR irradiation. Increased HIF‐1α expression in endothelial cells by SNP@UCM enhances angiogenesis in wound sites, promoting vascular endothelial growth factor (VEGF) secretion and cell proliferation and migration. SNP@UCM also enables early detection of wound infections and ROS‐mediated killing of bacteria. The potential clinical utility of SNP@UCM is further demonstrated in infected full‐thickness DU model under NIR irradiation. SNP@UCM is the first reported HIF‐1α‐stabilizing advanced nanomaterial, and further materials engineering might offer a facile, mechanism‐based method for clinical DU management. A subcutaneous injectable near‐infrared (NIR)‐triggered theranostic nitric oxide nanogenerator is bioengineered to maintain hypoxia‐inducible factor‐1α (HIF‐1α) stability by repressing ubiquitination‐mediated protein degradation and promote diabetic ulcer healing. This nanogenerator is also capable of early detection and elimination of wound infections.
Engineering therapeutic angiogenesis in impaired tissues is critical for chronic wound healing. Materials can be engineered to deliver specific biological cues that enhance angiogenesis. However, currently available materials have limitations for use in angiogenesis engineering since the complex inflammation environment of wounds requires spatiotemporal control. Immune cells are the central component of wound microenvironment and orchestrate immune responses to wound healing. This study presents a novel approach of using a delivery system comprising living Lactococcus, incorporated in a heparin-poloxamer thermoresponsive hydrogel, designed to bioengineer the wound microenvironment and enhance the angiogenesis in a highly dynamic-temporal manner. The living system can produce and protect vascular endothelial growth factor (VEGF) to increase proliferation, migration, and tube formation of endothelial cells, as well as secrete lactic acid to shift macrophages toward an anti-inflammatory phenotype, resulting in successful angiogenesis in diabetic wounds. Further, the delivery system confines the bacterial population to wounds, thereby minimizing the risk of systemic toxicities. Therefore, this living hydrogel system can be harnessed for safe and efficient delivery of therapeutics that drive the wound microenvironment toward rapid healing and may serve as a promising scaffold in regenerative medicine.
Nonhealing diabetic wounds are common complications for diabetic patients. Because chronic hypoxia prominently delays wound healing, sustained oxygenation to alleviate hypoxia is hypothesized to promote diabetic wound healing. However, sustained oxygenation cannot be achieved by current clinical approaches, including hyperbaric oxygen therapy. Here, we present a sustained oxygenation system consisting of oxygen-release microspheres and a reactive oxygen species (ROS)–scavenging hydrogel. The hydrogel captures the naturally elevated ROS in diabetic wounds, which may be further elevated by the oxygen released from the administered microspheres. The sustained release of oxygen augmented the survival and migration of keratinocytes and dermal fibroblasts, promoted angiogenic growth factor expression and angiogenesis in diabetic wounds, and decreased the proinflammatory cytokine expression. These effects significantly increased the wound closure rate. Our findings demonstrate that sustained oxygenation alone, without using drugs, can heal diabetic wounds.
Conductive hydrogels as flexible electronic devices, not only have unique attractions but also meet the basic need of mechanical flexibility and intelligent sensing. How to endow anisotropy and a wide application temperature range for traditional homogeneous conductive hydrogels and flexible sensors is still a challenge. Herein, a directional freezing method is used to prepare anisotropic MXene conductive hydrogels that are inspired by ordered structures of muscles. Due to the anisotropy of MXene conductive hydrogels, the mechanical properties and electrical conductivity are enhanced in specific directions. The hydrogels have a wide temperature resistance range of −36 to 25 °C through solvent substitution. Thus, the muscle‐inspired MXene conductive hydrogels with anisotropy and low‐temperature resistance can be used as wearable flexible sensors. The sensing signals are further displayed on the mobile phone as images through wireless technology, and images will change with the collected signals to achieve motion detection. Multiple flexible sensors are also assembled into a 3D sensor array for detecting the magnitude and spatial distribution of forces or strains. The MXene conductive hydrogels with ordered orientation and anisotropy are promising for flexible sensors, which have broad application prospects in human–machine interface compatibility and medical monitoring. Inspired by the ordered structure of muscles, MXene conductive hydrogels are anisotropic and can be used as wearable flexible sensors. The conductive hydrogels have the advantages of wide temperature tolerance range, high sensitivity and good stability. The flexible sensors can achieve motion detection through wireless technology and can be assembled into 3D arrays.
Diabetic wound healing still faces great challenges due to the excessive inflammation, easy infection, and impaired angiogenesis in wound beds. The immunoregulation of macrophages polarization toward M2 phenotype that facilitates the transition from inflammation to proliferation phase has been proved to be an effective way to improve diabetic wound healing. Herein, an M2 phenotype-enabled anti-inflammatory, antioxidant, and antibacterial conductive hydrogel scaffolds (GDFE) for producing rapid angiogenesis and diabetic wound repair are reported. The GDFE scaffolds are fabricated facilely through the dynamic crosslinking between polypeptide and polydopamine and graphene oxide. The GDFE scaffolds possess thermosensitivity, self-healing behavior, injectability, broad-spectrum antibacterial activity, antioxidant and anti-inflammatory ability, and electronic conductivity. GDFE effectively activates the polarization of macrophages toward M2 phenotype and significantly promotes the proliferation of dermal fibroblasts, the migration, and in vitro angiogenesis of endothelial cells through paracrine mechanisms. The in vivo results from a full-thickness diabetic wound model demonstrate that GDFE can rapidly promote the diabetic wound repair and skin regeneration, through fast anti-inflammation and angiogenesis and M2 macrophage polarization. This study provides highly efficient strategy for treating diabetic wound repair through designing the M2 polarization-enabled anti-inflammatory, antioxidant, and antibacterial bioactive materials.
Metabolic glycan labeling (MGL) followed by bioorthogonal chemistry provides a powerful tool for tumor imaging and therapy. However, selectively metabolic labeling of cells or tissues of interest remains a challenge. Particularly, owing to tumor heterogeneity including tumor subtypes and interpatient heterogeneity, it is far more difficult to realize tumor‐cell‐selective metabolic labeling for precise diagnosis. Inspired by nature, we designed azidosugar‐functionalized metal–organic frameworks camouflaged with cancer cell membranes to accomplish cancer‐cell‐selective MGL in vivo. With abundant receptors, this biomimetic platform not only selectively targets homotypic cells but also realizes different breast cancer subtype‐selective MGL. Moreover, the endo/lysosomal‐escaped ZIF‐8 can make azidosugar escape from lysosomes and accelerate its metabolic incorporation. This strategy also takes advantage of cancer‐tissue‐derived cell membranes, which may have huge potential for personalized diagnosis and therapy.
Effective healing of skin wounds is essential for our survival. Although skin has strong regenerative potential, dysfunctional and disfiguring scars can result from aberrant wound repair. Skin scarring involves excessive deposition and misalignment of ECM (extracellular matrix), increased cellularity, and chronic inflammation. Transforming growth factor-β (TGFβ) signaling exerts pleiotropic effects on wound healing by regulating cell proliferation, migration, ECM production, and the immune response. Although blocking TGFβ signaling can reduce tissue fibrosis and scarring, systemic inhibition of TGFβ can lead to significant side effects and inhibit wound re-epithelization. In this study, we develop a wound dressing material based on an integrated photo-crosslinking strategy and a microcapsule platform with pulsatile release of TGF-β inhibitor to achieve spatiotemporal specificity for skin wounds. The material enhances skin wound closure while effectively suppressing scar formation in murine skin wounds and large animal preclinical models. Our study presents a strategy for scarless wound repair.
Chronic wounds in diabetes undergo a lifetime risk of developing into diabetic foot ulcers. Oxygen is crucial to wound healing by regulating cell proliferation, migration, and neovascularization. However, current oxygen therapies, including hyperbaric oxygen (HBO) and topical gaseous oxygen (TGO), mainly employ gaseous oxygen delivery, which is much less effective in penetrating the skin. Here, we introduce an oxygen-producing patch, made of living microalgae hydrogel, which can produce dissolved oxygen. The superior performance of the patch that results from its dissolved oxygen delivery is >100-fold much more efficient than TGO penetrating the skin. Further experiments indicate that the patch could promote cell proliferation, migration, and tube formation in vitro, and improve chronic wound healing and the survival of skin grafts in diabetic mice. We believe that the microalgae-gel patch can provide continuous dissolved oxygen to improve chronic wound healing.
Macrophages (Mϕs) critically contribute to wound healing by coordinating inflammatory, proliferative, and angiogenic processes. A proper switch from proinflammatory M1 to anti‐inflammatory M2 dominant Mϕs accelerates the wound healing processes leading to favorable wound‐care outcomes. Herein, an exosome‐guided cell reprogramming technique is proposed to directly convert M1 to M2 Mϕs for effective wound management. The M2 Mϕ‐derived exosomes (M2‐Exo) induce a complete conversion of M1 to M2 Mϕs in vitro. The reprogrammed M2 Mϕs turn Arginase (M2‐marker) and iNOS (M1‐marker) on and off, respectively, and exhibit distinct phenotypic and functional features of M2 Mϕs. M2‐Exo has not only Mϕ reprogramming factors but also various cytokines and growth factors promoting wound repair. After subcutaneous administration of M2‐Exo into the wound edge, the local populations of M1 and M2 Mϕs are markedly decreased and increased, respectively, showing a successful exosome‐guided switch to M2 Mϕ polarization. The direct conversion of M1 to M2 Mϕs at the wound site accelerates wound healing by enhancing angiogenesis, re‐epithelialization, and collagen deposition. The Mϕ phenotype switching induced by exosomes possessing the excellent cell reprogramming capability and innate biocompatibility can be a promising therapeutic approach for various inflammation‐associated disorders by regulating the balance between pro‐ versus anti‐inflammatory Mϕs. An exosome‐guided cell reprogramming technique to directly convert M1 to M2 macrophages in situ is introduced as a promising therapeutic strategy for effective and rapid wound healing. With excellent cell reprogramming capabilities and biocompatibility, the exosome‐guided macrophage reprogramming technique can be applied not only to wound healing but also to various inflammation related diseases.
Nanomaterials with enzyme‐like activities, coined nanozymes, have been researched widely as they offer unparalleled advantages in terms of low cost, superior activity, and high stability. The complex structure and composition of nanozymes has led to extensive investigation of their catalytic sites at an atomic scale, and to an in‐depth understanding of the biocatalysis occurring. Single‐atom catalysts (SACs), characterized by atomically dispersed active sites, have provided opportunities for mimicking metalloprotease and for bridging the gap between natural enzymes and nanozymes. In this Minireview, we illustrate the unique properties of nanozymes and we discuss recent advances in the synthesis, characterization, and applications of SACs. Subsequently, we outline the impressive progress made in single‐atom nanozymes and we discuss their applications in sensing, degradation of organic pollutants, and in therapeutic roles. Finally, we present the major challenges and opportunities remaining for a successful marriage of nanozymes and SACs.
Tumor hypoxia compromises the therapeutic efficiency of photodynamic therapy (PDT) as the local oxygen concentration plays an important role in the generation of cytotoxic singlet oxygen (¹O2). Herein, a versatile mesoporous nanoenzyme (NE) derived from metal–organic frameworks (MOFs) is presented for in situ generation of endogenous O2 to enhance the PDT efficacy under bioimaging guidance. The mesoporous NE is constructed by first coating a manganese‐based MOFs with mesoporous silica, followed by a facile annealing process under the ambient atmosphere. After removing the mesoporous silica shell and post‐modifying with polydopamine and poly(ethylene glycol) for improving the biocompatibility, the obtained mesoporous NE is loaded with chlorin e6 (Ce6), a commonly used photosensitizer in PDT, with a high loading capacity. Upon the O2 generation through the catalytic reaction between the catalytic amount NE and the endogenous H2O2, the hypoxic tumor microenvironment is relieved. Thus, Ce6‐loaded NE serves as a H2O2‐activated oxygen supplier to increase the local O2 concentration for significantly enhanced antitumor PDT efficacy in vitro and in vivo. In addition, the NE also shows T2‐weighted magnetic resonance imaging ability for its in vivo tracking. This work presents an interesting biomedical use of MOF‐derived mesoporous NE as a multifunctional theranostic agent in cancer therapy.
Impaired diabetic wound healing represents a devastating and rapidly growing clinical problem associated with high morbidity, mortality, and recurrence rates. Engineering therapeutic angiogenesis in the wounded tissue is critical for successful wound healing. However, stimulating functional angiogenesis of the diabetic wound remains a great challenge, due to the oxidative damage and denaturation of bio-macromolecule-based angiogenic agents in the oxidative diabetic wound microenvironment. Here, we present a unique "seed-and-soil" strategy that circumvents the limitation by simultaneously reshaping the oxidative wound microenvironment into a proregenerative one (the "soil") and providing proangiogenic miRNA cues (the "seed") using an miRNA-impregnated, redox-modulatory ceria nanozyme-reinforced self-protecting hydrogel (PCN-miR/Col). The PCN-miR/Col not only reshapes the hostile oxidative wound microenvironment, but also ensures the structural integrity of the encapsulated proangiogenic miRNA in the oxidative microenvironment. Diabetic wounds treated with the PCN-miR/Col demonstrate a remarkably accelerated wound closure and enhanced quality of the healed wound as featured by highly ordered alignment of collagen fiber, skin appendage morphogenesis, functional new blood vessel growth, and oxygen saturation.
As a new generation of artificial enzymes, nanozymes have the advantages of high catalytic activity, good stability, low cost, and other unique properties of nanomaterials. Due to their wide range of potential applications, they have become an emerging field bridging nanotechnology and biology, attracting researchers in various fields to design and synthesize highly catalytically active nanozymes. However, the thorough understanding of experimental phenomena and the mechanisms beneath practical applications of nanozymes limits their rapid development. Herein, the progress of experimental and computational research of nanozymes on two issues over the past decade is briefly reviewed: (1) experimental development of new nanozymes mimicking different types of enzymes. This covers their structures and applications ranging from biosensing and bioimaging to therapeutics and environmental protection. (2) The catalytic mechanism proposed by experimental and theoretical study. The challenges and future directions of computational research in this field are also discussed.
Precisely carving of multi‐shelled manganese–cobalt oxide hollow dodecahedra (Co/Mn‐HD) with shell number up to three is achieved by a controlled calcination of the Mn‐doped zeolitic imidazolate framework ZIF‐67 precursor (Co/Mn‐ZIF). The unique multi‐shelled and polycrystalline structure not only provides a very large electrochemically active surface area (EASA), but also enhances the structural stability of the material. The residual C and N in the final structures might aid stability and increase their conductivity. When used in alkaline rechargeable battery, the triple‐shelled Co/Mn‐HD exhibits high electrochemical performance, reversible capacity (331.94 mAh g⁻¹ at 1 Ag⁻¹), rate performance (88 % of the capacity can be retained with a 20‐fold increase in current density), and cycling stability (96 % retention over 2000 cycles).
In the past few years, there have been many efforts underway to develop effective wound healing treatments for traumatic injuries. In particular, wound‐healing peptides (WHPs) and peptide‐grafted dressings hold great promise for novel therapeutic strategies for wound management. This study reports a topical formulation of a new synthetic WHP (REGRT, REG) embedded in a hyaluronic acid (HA)‐based hydrogel dressing for the enhancement of acute excisional wound repair. The copper‐free click chemistry is utilized to form biocompatible HA hydrogels by cross‐linking dibenzocyclooctyl‐functionalized HA with 4‐arm poly(ethylene glycol) (PEG) azide. The HA hydrogels are grafted with the REG peptide, a functional derivative of erythroid differentiation regulator1, displaying potent cell motility‐stimulating ability, thus sustainably releasing physiologically active peptides for a prolonged period. Combined with the traditional wound healing benefits of HA, the HA hydrogel embedded REG (REG‐HAgel) accelerates re‐epithelialization in skin wound healing, particularly by promoting migration of fibroblasts, keratinocytes, and endothelial cells. REG‐HAgels improve not only rate, but quality of wound healing with higher collagen deposition and more microvascular formation while being nontoxic. The peptide‐grafted HA hydrogel system can be considered as a promising new wound dressing formulation strategy for the treatment of different types of wounds with combinations of various natural and synthetic WHPs.
Cells secrete extracellular vesicles (EVs), exosomes and microvesicles, which transfer proteins, lipids and RNAs to regulate recipient cell functions. Skin pigmentation relies on a tight dialogue between keratinocytes and melanocytes in the epidermis. Here we report that exosomes secreted by keratinocytes enhance melanin synthesis by increasing both the expression and activity of melanosomal proteins. Furthermore, we show that the function of keratinocyte-derived exosomes is phototype-dependent and is modulated by ultraviolet B. In sum, this study uncovers an important physiological function for exosomes in human pigmentation and opens new avenues in our understanding of how pigmentation is regulated by intercellular communication in both healthy and diseased states.
One of the principal functions of any epithelium in the embryonic or adult organism is to act as a self-sealing barrier layer. From the earliest stages of development, embryonic epithelia are required to close naturally occurring holes and to fuse wherever two free edges are brought together, and at the simplest level that is precisely what the epidermis must do to repair itself wherever it is damaged. Parallels can be drawn between the artificially triggered epithelial movements of wound repair and the naturally occurring epithelial movements that shape the embryo during morphogenesis. Recent in vitro and in vivo wound-healing studies and analysis of paradigm morphogenetic movements in genetically tractable embryos, like those of Drosophila and Caenorhabditis elegans, have begun to identify both the signals that initiate these movements and the cytoskeletal machinery that drives motility. We are also gaining insight into the nature of the brakes and stop signals, and the mechanisms by which the confronting epithelial sheets knit together to form a seam.
As a burgeoning bioorthogonal reaction, the fluoride-mediated desilylation is capable of prodrug activation. However, due to the reactions lack of cell selectivity and unitary therapy modality, this strongly impedes their biomedical applications. Herein, we construct a cancer cell-selective biomimetic metal-organic framework (MOF)-F platform for prodrug activation and enhanced synergistic chemodynamic therapy (CDT). With cancer cell membranes camouflage, the designed biomimetic nanocatalyst displays preferential accumulation to homotypic cancer cells. Then, pH-responsive nanocatalyst releases fluoride ions and ferric ions. For activation of our designed prodrug tert-butyldimethyl silyl (TBS)-hydroxycamptothecin (TBSO-CPT), fluoride ions can desilylate TBS and cleave the designed silyl ether linker to synthesize the OH-CPT (10-hydroxycamptothecin) drug molecule, which effectively kills cancer cells. Intriguingly, the bioorthogonal-synthesized OH-CPT drug upregulates intracellular H2O2 by activating nicotinamide adenine dinucleotide phosphate oxidase (NOX), amplifying the released iron induced Fenton reaction for synergistic CDT. Both in vitro and in vivo studies demonstrate our strategy presents a versatile fluoride-activated bioorthogonal catalyst for cancer cell-selective drug synthesis. Our work may accelerate the biomedical applications of fluoride-activated bioorthogonal chemistry.
Type 1 diabetes (T1D) is an autoimmune disease in which immune cells destroy insulin-producing beta cells. The aetiology of this complex disease is dependent on the interplay of multiple heterogeneous cell types in the pancreatic environment. Here, we provide a single-cell atlas of pancreatic islets of 24 T1D, autoantibody-positive and nondiabetic organ donors across multiple quantitative modalities including ~80,000 cells using single-cell transcriptomics, ~7,000,000 cells using cytometry by time of flight and ~1,000,000 cells using in situ imaging mass cytometry. We develop an advanced integrative analytical strategy to assess pancreatic islets and identify canonical cell types. We show that a subset of exocrine ductal cells acquires a signature of tolerogenic dendritic cells in an apparent attempt at immune suppression in T1D donors. Our multimodal analyses delineate cell types and processes that may contribute to T1D immunopathogenesis and provide an integrative procedure for exploration and discovery of human pancreatic function. Fasolino et al. provide insights into ductal cell roles and type 1 diabetes pathogenesis using a pancreatic islet single-cell atlas generated by the Human Pancreas Analysis Program.
Wounds are one of the most common health issues, and the cost of wound care and healing has continued to increase over the past decade. The first step in wound healing is haemostasis, and the development of haemostatic materials that aid wound healing has accelerated in the past 5 years. Numerous haemostatic materials have been fabricated, composed of different active components (including natural polymers, synthetic polymers, silicon-based materials and metal-containing materials) and in various forms (including sponges, hydrogels, nanofibres and particles). In this Review, we provide an overview of haemostatic materials in wound healing, focusing on their chemical design and operation. We describe the physiological process of haemostasis to elucidate the principles that underpin the design of haemostatic wound dressings. We also highlight the advantages and limitations of the different active components and forms of haemostatic materials. The main challenges and future directions in the development of haemostatic materials for wound healing are proposed. Uncontrolled bleeding is a major cause of death, incentivizing the development of biomaterials that aid haemostasis and wound healing. This Review highlights the active components and forms of haemostatic materials, with a focus on their chemical design, and considers future trends in their development.
Single-atomic nanocatalysts/nanozymes (SACs/SAEs) have emerged as a research frontier on account of the maximum atom-utilization efficiency and well-defined localized structure. Metal-organic frameworks (MOFs) featuring structural diversity and functional tunability are promising host materials in constructing SACs/SAEs. Further, pyrolysis of MOF precursors under certain conditions can lead to the formations of MOF-derived SACs/SAEs. In this review, we first introduce the classification and enzymatic mechanisms of nanozymes, comprehensive characterization techniques for SACs/SAEs, and various synthetic methodologies of MOF-based SACs/SAEs. Next, we highlight the recent advances of MOF-based SACs/SAEs in the enzymatic healthcare area, i.e., cancer treatment, biosensing, antibacterial approaches, reactive oxygen species scavenging, and environmental protection. Finally, we summarize the insights we gain from these studies and discuss possible design principles and future challenges for a deeper understanding of this emerging field, thus offering great opportunities to leap over conventional nanozymes into a new era of next-generation biosafe SACs/SAEs.
ConspectusDiabetic foot ulcers (DFUs) are chronic wounds that develop in 30% of diabetic patients. In DFUs, the normal wound healing process consisting of inflammation, angiogenesis, and extracellular matrix (ECM) remodeling is dysregulated and stalled. Upon injury, neutrophils and monocytes arrive at the wound and secrete matrix metalloproteinase (MMP)-8 and reactive oxygen species (ROS). ROS activates nuclear factor kappa beta (NF-κB), which upregulates MMP-9. Monocytes become macrophages, secreting tumor growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) for angiogenesis, resulting in remodeling of the ECM. MMP-9 cleaves laminin for keratinocyte migration. MMP-8 is beneficial for remodeling the ECM and healing the wound. In DFUs, the excess unregulated MMP-9 is detrimental, destroying the ECM and preventing the wound from healing. DFUs are typically infected, many with biofilm-producing bacteria that are resistant to antibiotics. Infection increases the time for wound healing and the likelihood for a lower-limb amputation. Despite the use of antibiotics, amputations occur in 24.5% of patients with DFUs. Clearly, new strategies for treatment of DFUs are needed. With the use of an affinity resin that binds exclusively to the active forms of MMPs and proteomics, we identified two proteinases, MMP-8 and MMP-9, in wounds of diabetic mice and diabetic humans. With the use of selective inhibitors, gene ablation of MMP-9, and exogenous application of MMP-8, we demonstrated that MMP-8 is beneficial to wound repair and that MMP-9 prevents the diabetic wound from healing. Our research has shown that infection increases active MMP-9, increasing inflammation and decreasing angiogenesis. As a result, infected diabetic wounds take a longer time to heal than uninfected ones. We found that active MMP-9 and NF-κB increased in human DFUs with wound severity and infection. The best strategy for treatment of DFUs is to selectively inhibit the detrimental proteinase MMP-9 without affecting the beneficial MMP-8 so that the body can repair the wound. Lead optimization of the thiirane class of inhibitors led to the discovery of (R)-ND-336, a potent (19 nM) and selective (450-fold) MMP-9 inhibitor. (R)-ND-336 accelerated wound healing in diabetic mice by decreasing ROS and NF-κB, lowering inflammation, and increasing angiogenesis. (R)-ND-336 in combination with the antibiotic linezolid improved wound healing in infected diabetic mice by inhibiting MMP-9, which mitigated macrophage infiltration and increased angiogenesis, thereby restoring the normal wound healing process.
Oxygen is essential for the survival, function, and fate of mammalian cells. Oxygen tension controls cellular behaviour via metabolic programming, which in turn controls tissue regeneration, stem cell differentiation, drug metabolism, and numerous pathologies. Thus, oxygen-releasing biomaterials represent a novel and unique strategy to gain control over a variety of in vivo processes. Consequently, numerous oxygen-generating or carrying materials have been developed in recent years, which offer innovative solutions in the field of drug efficiency, regenerative medicine, and engineered living systems. In this review, we discuss the latest trends, highlight current challenges and solutions, and provide a future perspective on the field of oxygen-releasing materials.
Diabetic wound healing remains a critical challenge due to its vulnerability to multidrug-resistant (MDR) bacterial infection, as well as the hyperglycemic and oxidative wound microenvironment. Herein, an injectable multifunctional hydrogel (FEMI) was developed to simultaneously overcome these hurdles. The FEMI hydrogel was fabricated through a Schiff-based reaction between ε-poly lysine (EPL) coated MnO2 nanosheets (EM) and insulin loaded self-assembled aldehyde Pluronic F127 (FCHO) micelles. Through a synergistic combination of EPL and “nano-knife” like MnO2 nanosheets, the FEMI hydrogel exhibited extraordinary antimicrobial capacities against MDR bacteria. The MnO2 nanoenzyme reshaped the hostile oxidative wound microenvironment by decomposing the endogenous H2O2 into O2. Meanwhile, the pH/redox dual-responsive FEMI hydrogel achieved a sustained and spatiotemporal controlled release of insulin to regulate the blood glucose. Our FEMI hydrogel demonstrated an accelerated MDR bacteria-infected diabetic wound healing in vivo and represents a versatile strategy for healing a broad range of tissue damages caused by diabetes.
Diabetic wound healing and angiogenesis remain a worldwide challenge for both clinic and research. The use of adipose stromal cells (ASCs) derived exosomes delivered by bioactive dressing provides a potential strategy for repair diabetic wounds with less scar formation and fast healing. In this study, we fabricated an injectable adhesive thermosensitive multifunctional polysaccharide-based dressing (FEP) with sustained pH-responsive exosomes release for promoting angiogenesis and diabetic wound healing. The FEP dressing possessed multifunctional properties including efficient antibacterial activity/multidrug-resistant bacteria (MDRB), fast hemostatic ability, self-healing behavior, tissue-adhesive and good UV-shielding performance. [email protected] ([email protected]) can significantly enhance the proliferation, migration and tube formation of endothelial cells in vitro. In vivo results from a diabetic full-thickness cutaneous wound model showed that [email protected] dressing accelerated the wound healing by stimulating the angiogenesis process of the wound tissue. The enhanced cell proliferation, granulation tissue formation, collagen deposition and remodeling and re-epithelialization probably lead to the fast healing with less of scar tissue formation and skin appendages regeneration. This study showed that combining bioactive molecules into multifunctional dressing should have great potential in achieving satisfactory healing in diabetic and other vascular-impaired related wounds.
Photodynamic therapy (PDT) as a treatment method has many advantages such as minimal invasiveness, repeatable dosage and low systemic toxicity. Issues with conventional PDT agents include the limited availability of endogenous oxygen and difficulty in accumulation at tumor site, which hindered the successful treatment of tumor. Herein, we developed catalase-encapsulated hyaluronic acid-based nanoparticles loaded with adamantane modified photosensitizer for enhanced PDT of solid tumor. Chlorin e6 (Ce6) as the photosensitizer was modified with adamantane to yield adamantane modified Ce6 (aCe6). The obtained nanosystem (HA-CAT@aCe6) could target overly expressed CD44 receptors on cancer cells, supplying oxygen by converting endogenous hydrogen peroxide (H2O2) to oxygen, and improving PDT efficacy upon the light irradiation. HA-CAT@aCe6 nanoparticles showed high colloidal stability and mono-dispersity in aqueous solution. The uptake and targeting property of HA-CAT@aCe6 were demonstrated by confocal microscopy and flow cytometry in MDA-MB-231 cell line possessing overly expressed CD44 receptors. The encapsulated catalase was able to decompose the endogenous H2O2 to generate O2 in situ for relieving hypoxia in cells incubated under hypoxia conditions. Cell viability assays indicated that HA-CAT@aCe6 possessed minimal cytotoxicity in the dark, while presenting high cellular toxicity under 660 nm light irradiation at normoxic condition. As a result of the catalase capability in relieving hypoxia, HA-CAT@aCe6 also exhibited high cellular cytotoxicity under hypoxia condition. In vivo experiments revealed selective tumor accumulation of HA-CAT@aCe6 in MDA-MB-231 tumor bearing nude mice. Significant tumor regression was observed after intravenous injection of HA-CAT@aCe6 under light irradiation in comparison to the control system without loading catalase. Thus, HA-CAT@aCe6 demonstrated a great potential in overcoming hypoxia for targeted PDT.
Because of the high catalytic activities and substrate specificity, natural enzymes have been widely used in industrial, medical, and biological fields, etc. Although promising, they often suffer from intrinsic shortcomings such as high cost, low operational stability, and difficulties of recycling. To overcome these shortcomings, researchers have been devoted to the exploration of artificial enzyme mimics for a long time. Since the discovery of ferromagnetic nanoparticles with intrinsic horseradish peroxidase-like activity in 2007, a large amount of studies on nanozymes have been constantly emerging in the next decade. Nanozymes are one kind of nanomaterials with enzymatic catalytic properties. Compared with natural enzymes, nanozymes have the advantages such as low cost, high stability and durability, which have been widely used in industrial, medical, and biological fields. A thorough understanding of the possible catalytic mechanisms will contribute to the development of novel and high-efficient nanozymes, and the rational regulations of the activities of nanozymes are of great significance. In this review, we systematically introduce the classification, catalytic mechanism, activity regulation as well as recent research progress of nanozymes in the field of biosensing, environmental protection, and disease treatments, etc. in the past years. We also propose the current challenges of nanozymes as well as their future research focus. We anticipate this review may be of significance for the field to understand the properties of nanozymes and the development of novel nanomaterials with enzyme mimicking activities.
Many extracellular matrices (ECMs) have a filamentous architecture, which influences cell growth and phenotype and imparts tissues with specific properties. Man-made fibrillar hydrogels can function as biomimetic materials to reproduce the filamentous nature and properties of ECMs and to serve as scaffolds for 3D cell culture and tissue engineering. Different types of synthetic nanofibrillar hydrogels have been developed, with diverse mechanisms of assembly and a variety of physical properties and applications. In this Review, we explore the design and properties of biomimetic man-made nanofibrillar hydrogels. We discuss the assembly of peptides, block copolymer worm-like micelles and filamentous nanoparticles into fibrillar hydrogels and investigate the relationship between structure and physical as well as biochemical properties. Potential applications for 3D cell culture and tissue engineering are examined, and the properties and structure of natural and man-made fibrillar hydrogels are compared. Finally, we critically assess current challenges and future directions of the field.
We report a supramolecular strategy to prepare conductive hydrogels with outstanding mechanical and electrochemical properties, which are utilized for flexible solid-state supercapacitors (SCs) with high performance. The supramolecular assembly of polyaniline and polyvinyl alcohol through dynamic boronate bond yields the polyaniline-polyvinyl alcohol hydrogel (PPH), which shows remarkable tensile strength (5.3 MPa) and electrochemical capacitance (928 F g(-1) ). The flexible solid-state supercapacitor based on PPH provides a large capacitance (306 mF cm(-2) and 153 F g(-1) ) and a high energy density of 13.6 Wh kg(-1) , superior to other flexible supercapacitors. The robustness of the PPH-based supercapacitor is demonstrated by the 100 % capacitance retention after 1000 mechanical folding cycles, and the 90 % capacitance retention after 1000 galvanostatic charge-discharge cycles. The high activity and robustness enable the PPH-based supercapacitor as a promising power device for flexible electronics.
Chronic diseases confer tissue and organ damage that reduce quality of life and are largely refractory to therapy. Although stem cells hold promise for treating degenerative diseases by 'seeding' injured tissues, the regenerative capacity of stem cells is influenced by regulatory networks orchestrated by local immune responses to tissue damage, with macrophages being a central component of the injury response and coordinator of tissue repair. Recent research has turned to how cellular and signaling components of the local stromal microenvironment (the 'soil' to the stem cells' seed), such as local inflammatory reactions, contribute to successful tissue regeneration. This Review discusses the basic principles of tissue regeneration and the central role locally acting components may play in the process. Application of seed-and-soil concepts to regenerative medicine strengthens prospects for developing cell-based therapies or for promotion of endogenous repair.