Background: Wound healing and scarring are driven by transforming growth factor-␤1 (TGF-␤1)-dependent fibroblast to myofibroblast differentiation. Results: Cell surface CD44 and epidermal growth factor receptor (EGFR) co-localize in lipid rafts to signal through mitogenactivated protein kinase 1/2 (ERK1/2) and Ca 2ϩ /calmodulin kinase II (CaMKII). Conclusion: CD44 moves into lipid rafts in a TGF-␤1-and hyaluronan-dependent manner, co-localizes with EGFR, and triggers differentiation. Significance: This pathway presents novel targets for the therapy of wound-healing and fibrosis.

Implanted scaffolds with inductive niches can facilitate the recruitment and differentiation of host cells, thereby enhancing endogenous tissue regeneration. Extracellular matrix (ECM) scaffolds derived from cultured cells or natural tissues exhibit superior biocompatibility and trigger favourable immune responses. However, the lack of hierarchical porous structure fails to provide cells with guidance cues for directional migration and spatial organization, and consequently limit the morpho-functional integration for oriented tissues. Here, we engineer ECM scaffolds with parallel microchannels (ECM-C) by subcutaneous implantation of sacrificial templates, followed by template removal and decellularization. The advantages of such ECM-C scaffolds are evidenced by close regulation of in vitro cell activities, and enhanced cell infiltration and vascularization upon in vivo implantation. We demonstrate the versatility and flexibility of these scaffolds by regenerating vascularized and innervated neo-muscle, vascularized neo-nerve and pulsatile neo-artery with functional integration. This strategy has potential to yield inducible biomaterials with applications across tissue engineering and regenerative medicine.

Development of enzyme mimics for the scavenging of excessive mitochondrial superoxide (O2•−) can serve as an effective strategy in the treatment of many diseases. Here, protein reconstruction technology and nanotechnology is taken advantage of to biomimetically create an artificial hybrid nanozyme. These nanozymes consist of ferritin‐heavy‐chain‐based protein as the enzyme scaffold and a metal nanoparticle core as the enzyme active center. This artificial cascade nanozyme possesses superoxide dismutase‐ and catalase‐like activities and also targets mitochondria by overcoming multiple biological barriers. Using cardiac ischemia‐reperfusion animal models, the protective advantages of the hybrid nanozymes are demonstrated in vivo during mitochondrial oxidative injury and in the recovery of heart functionality following infarction via systemic delivery and localized release from adhesive hydrogels (i.e., cardiac patch), respectively. This study illustrates a de novo design strategy in the development of enzyme mimics and provides a promising therapeutic option for alleviating oxidative damage in regenerative medicine.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. In vivo tracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV−hydrogel interaction was mediated by RGD−integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.

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Stem cell therapy has proven to be an attractive solution for the treatment of degenerative diseases or injury. However, poor cell engraftment and survival within injured tissues limits the successful use of stem cell therapy within the clinical setting. Nitric oxide (NO) is an important signaling molecule involved in various physiological processes. Emerging evidence supports NO's diverse roles in modulating stem cell behavior, including survival, migration, differentiation, and paracrine secretion of proregenerative factors. Thus, there has been a shift in research focus to concentrate efforts on the delivery of therapeutic concentration ranges of NO to the target tissue sites. Combinatory therapies utilizing biomaterials that control NO generation and support stem cell delivery can be holistic and synergistic approaches to significantly improve tissue regeneration. Here, the focus is on recent developments of various therapeutic platforms, engineered to both transport NO and to enhance stem‐cell‐mediated regeneration of damaged tissues. New and emerging revelations of how the stem cell microenvironment can be regulated by NO‐releasing biomaterials are also highlighted.

Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.

the intrinsic characteristics of nano materials, nanozymes have potential widespread applications within the fields of biosensing, [2] antibacterials, [3] environ mental pollution, [4] and disease therapy. [5] Since our discovery of ferromagnetic nanoparticles with intrinsic peroxidase like activity in 2007, [6] there have been thousands of publications that reported on enzymemimicking activities of nanoma terials, which involve at least six classes of enzymemimicry. [7] According to the litera ture, different nanomaterials can intrinsi cally possess the same enzymemimicking activities, [8] and certain types of nano materials tend to exhibit differential enzymelike catalytic activities. [9] The het erogeneous results reveal the complexity and diversity of nanozymes in terms of catalytic capacity. [10] Indeed, the particle property relationship of nanozymes is complicated, with a current lack of fun damental understanding. Furthermore, the synthesis of nanozymes with desired characteristics are generally determined by trial and error, and based on intui tion and experience, which are timeconsuming, laborious and resourceintensive.As a branch of artificial intelligence, machine learning aims to develop computational algorithms to infer mathematical An abundant number of nanomaterials have been discovered to possess enzyme-like catalytic activity, termed nanozymes. It is identified that a variety of internal and external factors influence the catalytic activity of nanozymes. However, there is a lack of essential methodologies to uncover the hidden mechanisms between nanozyme features and enzyme-like activity. Here, a data-driven approach is demonstrated that utilizes machine-learning algorithms to understand particle-property relationships, allowing for classification and quantitative predictions of enzyme-like activity exhibited by nanozymes. High consistency between predicted outputs and the observations is confirmed by accuracy (90.6%) and R 2 (up to 0.80). Furthermore, sensitive analysis of the models reveals the central roles of transition metals in determining nanozyme activity. As an example, the models are successfully applied to predict or design desirable nanozymes by uncovering the hidden relationship between different periods of transition metals and their enzyme-like performance. This study offers a promising strategy to develop nanozymes with desirable catalytic activity and demonstrates the potential of machine learning within the field of material science.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adma.202201736.