Ferroptosis, an iron-based cell-death pathway, has recently attracted great attention owing to its effectiveness in killing cancer cells. Previous investigations focused on the development of iron-based nanomaterials to induce ferroptosis in cancer cells by the up-regulation of reactive oxygen species (ROS) generated by the wellknown Fenton reaction. Herein, we report a ferroptosisinducing agent based on arginine-rich manganese silicate nanobubbles (AMSNs) that possess highly efficient glutathione (GSH) depletion ability and thereby induce ferroptosis by the inactivation of glutathione-dependent peroxidases 4 (GPX4). The AMSNs were synthesized via a one-pot reaction with arginine (Arg) as the surface ligand for tumor homing. Subsequently, a significant tumor suppression effect can be achieved by GSH depletion-induced ferroptosis. Moreover, the degradation of AMSNs during the GSH depletion contributed to T 1 -weighted magnetic resonance imaging (MRI) enhancement as well as on-demand chemotherapeutic drug release for synergistic cancer therapy. We anticipate that the GSH-depletion-induced ferroptosis strategy by using manganese-based nanomaterials would provide insights in designing nanomedicines for tumor-targeted theranostics.

Recent advances in nanomedicine have facilitated the development of potent nanomaterials with intrinsic enzyme-like activities (nanozymes) for cancer therapy. However, it remains a great challenge to fabricate smart nanozymes that precisely perform enzymatic activity in tumor microenvironment without inducing off-target toxicity to surrounding normal tissues. Herein, we report on designed fabrication of biodegradation-medicated enzymatic activity-tunable molybdenum oxide nanourchins (MoO3–x NUs), which selectively perform therapeutic activity in tumor microenvironment via cascade catalytic reactions, while keeping normal tissues unharmed due to their responsive biodegradation in physiological environment. Specifically, the MoO3–x NUs first induce catalase (CAT)-like reactivity to decompose hydrogen peroxide (H2O2) in tumor microenvironment, producing a considerable amount of O2 for subsequent oxidase (OXD)-like reactivity of MoO3–x NUs; a substantial cytotoxic superoxide radical (·O2 –) is thus generated for tumor cell apoptosis. Interestingly, once exposed to neutral blood or normal tissues, MoO3–x NUs rapidly lose the enzymatic activity via pH-responsive biodegradation and are excreted in urine, thus ultimately ensuring safety. The current study demonstrates a proof of concept of biodegradation-medicated in vivo catalytic activity-tunable nanozymes for tumor-specific cascade catalytic therapy with minimal off-target toxicity.

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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.

Iron oxide nanoparticle (IONP)-based magnetic resonance imaging (MRI) contrast agents have been widely used for the diagnosis of hepatic lesions. However, current IONP-based liver-specific MRI contrast agents rely on single-phase contrast enhancement of the normal liver, which is not sensitive enough to detect early stage small hepatocellular carcinomas (HCCs). We herein report i-motif DNA-assisted pH-responsive iron oxide nanocluster assemblies (termed RIAs), which provide an inverse contrast enhancemt effect to improve the distinction between normal liver and target HCC tissues. The acidic pH of the tumor microenvironment triggers the disassembly of the RIAs, which leads to a drastic decrease in their relaxivity ratio ( r/ r), thus converting the RIAs from a T2 to T1 contrast agent. This inverse contrast enhancement of normal liver darkening and HCC brightening under T1 imaging mode was validated on an orthotopic HCC model. Our design provides a novel strategy for the exploitation of the next-generation intelligent MRI contrast agents.