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Rationale: Acute kidney injury (AKI) is associated with aberrant generation of oxidative species and inflammation, leading to high mortality of in-hospitalized patients. Although N-acetylcysteine (NAC) showed positive effects in alleviating contrast-induced AKI, the clinical applications are strongly restrained due to the low bioavailability, low renal accumulation, short renal retention time, and high dosage-induced toxicity. Methods: We addressed the clinical dilemma of NAC by developing ultrasmall gold nanoclusters (1-2 nm) capped with NAC (denoted as Au NCs-NAC) as a nanozyme-based antioxidant defense system for AKI alleviation. Rhabdomyolysis-induced AKI mice model was developed, and the same dose of free NAC (as a control) and NAC onto Au NCs (Au NCs-NAC) was used for in vivo investigation of AKI restoration. Results: The as-developed gold nanozyme exhibited high bioavailability and good physicochemical stability as compared to NAC. Meanwhile, Au NCs-NAC showed broad-spectrum antioxidant activity of Au NCs-NAC, offering in vitro renoprotective effects, as well as macrophages by relieving inflammation under hydrogen peroxide or lipopolysaccharide stimulation. Notably, owing to the smaller size than kidney threshold (5.5 nm), Au NCs-NAC displayed preferential renal enrichment (< 2 h) and longer retention (> 24 h) in AKI mice as revealed by fluorescence imaging, thereby largely enhancing the restoration of renal function in AKI mice than free NAC by protecting the kidneys from oxidative injury and inflammation without systemic toxicity, as demonstrated by tissues staining, inflammatory cytokines and biomarkers detection, and mice survival rate. Conclusion: Owing to the synergistic anti-inflammatory/antioxidative effects, and enhanced bioavailability and renal accumulation/retention, Au NCs-NAC displayed far superior therapeutic performance than NAC alone. This work will facilitate the development of high-performance antioxidative nanoplatforms, as well as overcome the clinical limitations of small molecular drugs for AKI treatment and other inflammatory diseases.

Background Acute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine antioxidant therapy has been used to alleviate AKI. Herein, we synthesized ultrasmall Prussian blue nanozymes (PB NZs, 4.5 nm) as theranostic agents for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided AKI treatment. Results PB NZs exhibited multi-enzyme mimetic abilities, promoting the effective elimination of RONS both in vitro and in vivo. Moreover, benefiting from their imaging contrast properties, the rapid renal accumulation of PB NZs was verified by in vivo PA/MR dual-modal imaging. Due to their excellent enrichment in the kidney and unique multi-enzyme mimetic abilities, ultrasmall PB NZs displayed superior AKI treatment efficacy compared with that of amifostine in two clinically relevant types of AKI induced murine models (either by rhabdomyolysis or cisplatin). Conclusion Our findings suggested ultrasmall PB NZs, as nanozyme theranostics, have great potential for AKI management. Graphic abstract

Rhabdomyolysis-induced acute kidney injury (AKI) is closely related to abundant reactive oxygen species (ROS). Owing to the multi-enzymatic activity and broad-spectrum ROS scavenging capacity of ceria nanoparticles (ceria NPs), herein, we report ultrasmall citric acid modified ceria nanozymes (3-4 nm) as antioxidants to alleviate rhabdomyolysis-induced AKI through removing excessive ROS. The as-prepared ceria NPs exhibited multi-enzymatic properties such as peroxidase, catalase, and superoxide dismutase, offering efficient protection of renal cells against H2O2 stimulation in vitro. Moreover, due to their ultrasmall size, ceria NPs could efficiently accumulate in the kidneys, thus protecting renal cells against ROS in vivo. Our results present ultrasmall ceria nanozymes as antioxidants for rhabdomyolysis-induced AKI alleviation, which shows great potential in clinic.

Acute kidney injury (AKI) is a kind of kidney disease with a high mortality rate, and is predominantly associated with abundant endogenous reactive oxygen/nitrogen species (RONS). However, there are no universal clinical treatment options currently. Development of antioxidants with high kidney enrichment is highly desired to prevent AKI. As a promising new artificial enzyme , nanozymes have attracted extensive attention over the past decade because of their commendable advantages over natural and traditional artificial enzymes. In this study, we reported ultrasmall polyvinylpyrrolidone-coated iridium nanoparticles (denoted as Ir NPs-PVP, 1.5 nm) as multi-enzyme mimetic to scavenge a variety of RONS, offering an efficient RONS-induced cellular protection. Meanwhile, computed tomography and inductively coupled plasma mass spectrometry demonstrated preferential renal uptake of Ir NPs-PVP following intravenous administration, leading to alleviate clinical symptoms in mice subjected to rhabdomyolysis- or cis-platinum-induced AKI. Impressively, ultrasmall Ir NPs-PVP exhibit relatively low systemic side effects in vivo due to rapid renal clearance via urine. Our work presents the clinically translatable potential of ultrasmall nanozymes for AKI management.

Acute kidney injury (AKI) is frequently triggered by abundant reactive oxygen/nitrogen species (RONS) and leads to high morbidity and mortality in clinic. Unfortunately, the current clinical treatment options are only limited to supportive care, and hence, the development of nano-antioxidants with high kidney enrichment is an attractive novel strategy for AKI management. Herein, self-assembled ultrasmall nanodots are reported that consist of iron ion, gallic acid, and polyvinylpyrrolidone (denoted as FGP nanodots) as broad-spectrum RONS scavengers to alleviate both glycerinum- and cis-platinum- induced AKI in mice. Ultrasmall FGP nanodots (≈3.5 nm) offer efficient protection in vitro and reduce cellular apoptosis after H2 O2 stimulation by eliminating various RONS including hydroxyl radical (·OH), superoxide anion (·O2 - ), nitric oxide (NO), and peroxynitrite (ONOO- ), etc. In vivo duplex magnetic resonance/fluorescence imaging demonstrates preferential accumulation of FGP nanodots in the kidneys with rapid renal clearance through urine. Importantly, FGP nanodots exhibit remarkable RONS consumption in vivo with enhanced biocompatibility and biodegradability, resulting in superior therapeutic effect than small molecule drug (Amifostine) in two AKI mouse models. This study presents the promising potential of ultrasmall self-assembled FGP nanodots as imaging contrast agent and broad-spectrum antioxidant nanomedicine for AKI theranotics.