Clinically translatable gold nanozymes with broad spectrum antioxidant and anti-inflammatory activity for alleviating acute kidney injury

Abstract

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.

Nanodrugs alleviate acute kidney injury: Manipulate RONS at kidney

“…More importantly, lots of noble metal nanoparticles have high intrinsic catalytic activity due to their incompletely filled d-electron orbitals and small energy level spacing [ 212 ]. Currently, ultra-small-sized gold [ 198 ], platinum [ 195 ], Ir [ 196 ], and Ru [ 197 ] nanoparticles have been developed for the treatment of AKI, and these nanoparticles are often passively targeted to renal tissue to eliminate various RONS thanks to their variety of antioxidant enzyme properties. Among them, platinum nanoparticles (Pt NPs) have attracted much attention for their broad-spectrum and efficient RONS quenching activity by mimicking a variety of enzymes, including CAT, SOD, and NADH-coenzyme Q reductase.…”

“…14 C). Very recently, Zhang et al employed the NAC as a reductant and capping to synthesize ultrasmall gold nanoclusters (Au NCs) to provide effective AKI alleviation [ 198 ]. Au NCs had multienzyme mimetic properties like POD, SOD, and CAT.…”

Structure design mechanisms and inflammatory disease applications of nanozymes

“…These findings proved that ultrasmall Ir NPs-PVP have good compatibility and low toxicity, and have enormous promise for treating cisplatin-induced AKI and RM-AKI. Zhang et al also designed ultrasmall gold nanoclusters capped with NAC (Au-NAC) with SOD-like, CAT-like, and POD-like activities for RM-AKI treatment 184 (Fig. 17(d)).…”

Advances in the modulation of ROS and transdermal administration for anti-psoriatic nanotherapies

“…Gold nanoparticles (Au NPs) have shown good biocompatibility, water-solubility, catalytic activity and great potential as self-therapeutic nanosystems for drug delivery platforms against inflammatory disorders, including AKI and RA due to their anti-inflammatory and antioxidative performances [ 179 , 180 ]. It has been reported that the tunable bio-effects of Au NPs differ across research due to the application of regulatory particle sizes and surface modification [ 181 ].…”