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.

Ferroptosis is a regulated iron-dependent cell death characterized by the accumulation of lipid peroxidation. A myriad of facets linking amino acid, lipid, redox, and iron metabolisms were found to drive or to suppress the execution of ferroptosis. However, how the cells decipher the diverse pro-ferroptotic stress to activate ferroptosis remains elusive. Here, we report that protein O-GlcNAcylation, the primary nutrient sensor of glucose flux, orchestrates both ferritinophagy and mitophagy for ferroptosis. Following the treatment of ferroptosis stimuli such as RSL3, a commonly used ferroptosis inducer, there exists a biphasic change of protein O-GlcNAcylation to modulate ferroptosis. Pharmacological or genetic inhibition of O-GlcNAcylation promoted ferritinophagy, resulting in the accumulation of labile iron towards mitochondria. Inhibition of O-GlcNAcylation resulted in mitochondria fragmentation and enhanced mitophagy, providing an additional source of labile iron and rendering the cell more sensitive to ferroptosis. Mechanistically, we found that de-O-GlcNAcylation of the ferritin heavy chain at S179 promoted its interaction with NCOA4, the ferritinophagy receptor, thereby accumulating labile iron for ferroptosis. Our findings reveal a previously uncharacterized link of dynamic O-GlcNAcylation with iron metabolism and decision-making for ferroptosis, thus offering potential therapeutic intervention for fighting disease.

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.

Restoration of sufficient blood supply for the treatment of ischemia remains a significant scientific and clinical challenge. Here, a cell‐like nanoparticle delivery technology is introduced that is capable of recapitulating multiple cell functions for the spatiotemporal triggering of vascular regeneration. Specifically, a copper‐containing protein is successfully prepared using a recombinant protein scaffold based on a de novo design strategy, which facilitates the timely release of nitric oxide and improved accumulation of particles within ischemic tissues. Through closely mimicking physiological cues, the authors demonstrate the benefits of bioactive factors secreted from hypoxic stem cells on promoting angiogenesis. Following this cell‐mimicking manner, artificial hybrid nanosized cells (Hynocell) are constructed by integrating the hypoxic stem cell secretome into nanoparticles with surface coatings of cell membranes fused with copper‐containing protein. The Hynocell, hybridized with different cell‐derived components, provides synergistic effects on targeting ischemic tissues and promoting vascular regeneration in acute hindlimb ischemia and acute myocardial infarction models. This study offers new insights into the utilization of nanotechnology to potentiate the development of cell‐free therapeutics.

Biomimetic design of nanomaterials with enzyme‐like characteristics has emerged as a promising method for the generation of novel therapeutics. However, synthesis of nanomaterials while maintaining a high degree of control over both geometry and valency poses a prominent challenge. Herein, the authors introduce a nanomaterial‐based synthetic biology strategy for accurate and quantitative tailoring of high‐ordered nanostructures that uses a “bottom‐up” hierarchical incorporation of protein building blocks. The assembled nano‐oligomers possessed tunable protein motifs and multivalent binding domains, which facilitated prolonged blood circulation time, accumulation within tumor cells through direct targeting of cell receptors, and deep tumor tissue penetration via a transcytosis mechanism. Using these protein/protein nano‐oligomers as scaffolds, the authors created a new series of artificial nano‐scaled metalloenzymes (nanozymes) by the in situ incorporation of metal nanoclusters within the cavity of the protein nanocages. Nanozymes were capable of mimicking peroxidase‐like activity and generated cytotoxic free radicals. Compared to nanozyme alone, the systemic delivery of oligomeric nanozymes demonstrated significantly enhanced therapeutic and anti‐tumor benefits. This study shows a new insight into nanotechnology by taking advantage of synthetic biotechnology.