A Thrombin-Activated Peptide-Templated Nanozyme for Remedying Ischemic Stroke via Thrombolytic and Neuroprotective Actions.

Ischemic stroke (IS) is one of the most common causes of disability and death. Thrombolysis and neuroprotection are two current major therapeutic strategies to overcome ischemic and reperfusion damage. In this work, a novel peptide-templated manganese dioxide nanozyme (PNzyme/MnO2 ) is designed that integrates the thrombolytic activity of functional peptides with the reactive oxygen species scavenging ability of nanozymes. Through self-assembled polypeptides that contain multiple functional motifs, the novel peptide-templated nanozyme is able to bind fibrin in the thrombus, cross the blood-brain barrier, and finally accumulate in the ischemic neuronal tissues, where the thrombolytic motif is "switched-on" by the action of thrombin. In mice and rat IS models, the PNzyme/MnO2 prolongs the blood-circulation time and exhibits strong thrombolytic action, and reduces the ischemic damages in brain tissues. Moreover, this peptide-templated nanozyme also effectively inhibits the activation of astrocytes and the secretion of proinflammatory cytokines. These data indicate that the rationally designed PNzyme/MnO2 nanozyme exerts both thrombolytic and neuroprotective actions. Giving its long half-life in the blood and ability to target brain thrombi, the biocompatible nanozyme may serve as a novel therapeutic agent to improve the efficacy and prevent secondary thrombosis during the treatment of IS.

Ferritin nanocage: A promising and designable multi-module platform for constructing dynamic nanoassembly-based drug nanocarrier.

Ferritin has been widely recognized as an ideal drug delivery vehicle owing to its unique cage-like structure. Coupled with intrinsic targeting ability and excellent biosafety, ferritin-based drug delivery system, recently coined as ferritin drug carrier (FDC), has sparked great interest among researchers and shown promising application potential in the biomedical field. However, the flexibility and accuracy of traditional FDCs are limited when facing with complex disease microenvironments. To meet the fast-growing requirements for precision medicine, ferritin can serve as a designable multi-module platform to fabricate smarter FDC, which we introduce here as dynamic nanoassembly-based ferritin drug carrier (DNFDC). Compared to conventional FDC, DNFDCs directly integrate required functions into their nanostructure, which can achieve dynamic transformation upon stimuli to specifically activate and exert therapeutic functions at targeted sites. In this review, we summarize the superior characteristics of ferritin that contribute to the on-demand design of DNFDC and outline the current advances in DNFDC. Moreover, the potential research directions and challenges are also discussed here. Hopefully, this review may inspire the future development of DNFDC.

Nanozyme for tumor therapy: Surface modification matters.

As the next generation of artificial enzymes, nanozymes have shown unique properties compared to its natural counterparts, such as stability in harsh environment, low cost, and ease of production and modification, paving the way for its biomedical applications. Among them, tumor catalytic therapy mediated by the generation of reactive oxygen species (ROS) has made great progress mainly from the peroxidase-like activity of nanozymes. Fe3O4 nanozymes, the earliest type of nanomaterial discovered to possess peroxidase-like activity, has consequently received wide attention for tumor therapy due to its ROS generation ability and tumor cell killing ability. However, inconsistent results of cytotoxicity were observed between different reports, and some even showed the scavenging of ROS in some cases. By collectively studying these inconsistent outcomes, we raise the question whether surface modification of Fe3O4 nanozymes, either through affecting peroxidase activity or by affecting the biodistribution and intracellular fate, play an important role in its therapeutic effects. This review will go over the fundamental catalytic mechanisms of Fe3O4 nanozymes and recent advances in tumor catalytic therapy, and discuss the importance of surface modification. Employing Fe3O4 nanozymes as an example, we hope to provide an outlook on the improvement of nanozyme-based antitumor activity.

Self-activated in vivo therapeutic cascade of erythrocyte membrane-cloaked iron-mineralized enzymes.

Biomineralization of enzymes for in vivo diagnosis and treatment of diseases remain a considerable challenge, due to their severe reaction conditions and complicated physiological environment. Herein, we reported a biomimetic enzyme cascade delivery nanosystem, tumor-targeted erythrocyte membrane (EM)-cloaked iron-mineralized glucose oxidases (GOx-Fe0@EM-A) for enhancing anticancer efficacy by self-activated in vivo cascade to generate sufficient high toxic •OH at tumor site. Methods: An ultra-small Fe0 nanoparticle (Fe0NP) was anchored in the inner cavity of glucose oxidase (GOx) to form iron-mineralized glucose oxidase (GOx-Fe0) as a potential tumor therapeutic nanocatalyst. Moreover, erythrocyte membrane cloaking delivery of GOx-Fe0in vivo was designed to effectively accumulate ultra-small GOx-Fe0 at tumor site. Results: GOx-Fe0@EM-A had satisfactory biocompatibility and light-trigged release efficiency. Erythrocyte membrane cloaking of GOx-Fe0@EM-A not only prolongs blood circulation but also protects in vivo enzyme activity of GOx-Fe0; Tumor targeting of GOx-Fe0@EM-A endowed preferential accumulation at tumor site. After NIR light irradiation at tumor site, erythrocyte membrane of GOx-Fe0@EM-A was ruptured to achieve light-driven release and tumor deep penetration of ultra-small nanosize GOx-Fe0 by the photothermal effect of ICG. Then, GOx-Fe0 occurred self-activated in vivo cascade to effectively eradicate tumor by producing the highly cumulative and deeply penetrating •OH at tumor site. Conclusion: Tumor-targeted erythrocyte membrane-cloaked iron-mineralized glucose oxidase (GOx-Fe0@EM-A) exhibits a promising strategy for striking antitumor efficacy by light-driven tumor deep penetration and self-activated therapeutic cascade.