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We report the "water-in-oil-in-water" preparation of kidney injury molecule-1-targeting supramolecular chemiluminescence (CL) reporters (PCCS), consisting of L-serine-modified poly(lactic-co-glycolic) acid (PLGA)-encapsulated peroxyoxalate (CPPO), chlorin e6 (Ce6) and superoxide dismutase (SOD), for early diagnosis and amelioration of acute kidney injury (AKI). In this system, O 2 ⋅ - , a biomarker of AKI, triggers the oxidation of CPPO to 1,2-dioxetanedione and subsequent CL emission via CL resonance energy transfer to Ce6. The L-serine-modified PLGA stabilizes CPPO and Ce6 via noncovalent interactions, promoting long-lived CL (half-lives: ≈1000 s). Transcriptomics analysis shows that PCCS reporters reduce the inflammatory response through glutathione metabolism and inhibition of the tumor necrosis factor signaling pathway. The reporters are able to non-invasively detect AKI at least 12 h earlier than current assays, and their antioxidant properties allow simultaneous treatment of AKI., (© 2023 Wiley-VCH GmbH.)

Herein, we designed and synthesized a novel microRNA (miR)-responsive nanoantenna capable of early diagnosis and smart treatment of acute kidney injury (AKI). The nanoantenna was made of two miniature gold nanorods (AuNRs) ( e.g. , length: ∼48 nm; width: ∼9 nm) linked together by a rectangular DNA origami nanostructure (rDONs) scaffold ( e.g. , length: ∼90 nm; width: ∼60 nm) (rDONs@AuNR dimer). The surface plasmon resonance peak of the constructed nanoantenna is located within the NIR-II window ( e.g. , ∼1060 nm), thus guaranteeing photoacoustic (PA) imaging of the nanoantenna in deep tissues. Intriguingly, the nanoantenna displayed exclusive kidney retention in both healthy mice and ischemia reperfusion-induced AKI mice by leveraging the kidney-targeting ability of rDONs. Distinguished from the stable signals in the healthy mice, the PA signals of the nanoantenna would turn down in the AKI mice due to the AuNR detached from rDONs upon interaction with miR-21, which were up-expressed in AKI mice. The limit of detection toward miR-21 was down to 2.8 nM, enabling diagnosis of AKI as early as 10 min post-treatment with ischemia reperfusion, around 2 orders of magnitude earlier than most established probes. Moreover, the naked rDON scaffold generated by AKI could capture more reactive oxygen species ( e.g. , 1.5-fold more than rDONs@AuNR dimer), alleviating ischemic AKI. This strategy provided a new avenue for early diagnosis and smart treatment of AKI.

We report the "water‐in‐oil‐in‐water" preparation of kidney injury molecule‐1‐targeting supramolecular chemiluminescence (CL) reporters (PCCS), consisting of L‐serine‐modified poly(lactic‐co‐glycolic) acid (PLGA)‐encapsulated peroxyoxalate (CPPO), chlorin e6 (Ce6) and superoxide dismutase (SOD), for early diagnosis and amelioration of acute kidney injury (AKI). In this system, O2⋅−, a biomarker of AKI, triggers the oxidation of CPPO to 1,2‐dioxetanedione and subsequent CL emission via CL resonance energy transfer to Ce6. The L‐serine‐modified PLGA stabilizes CPPO and Ce6 via noncovalent interactions, promoting long‐lived CL (half‐lives: ≈1000 s). Transcriptomics analysis shows that PCCS reporters reduce the inflammatory response through glutathione metabolism and inhibition of the tumor necrosis factor signaling pathway. The reporters are able to non‐invasively detect AKI at least 12 h earlier than current assays, and their antioxidant properties allow simultaneous treatment of AKI. [ABSTRACT FROM AUTHOR]