Current advances in nanomedicine-based therapies for acute kidney injury

Citation: Ruimiao Chang, Xinying Qu, Yuting Ye, Ying Qu, Bingyang Chu, Zhiyong Qian. Current advances in nanomedicine-based therapies for acute kidney injury[J]. Chinese Chemical Letters, 2025, 36(10): 110802. doi: 10.1016/j.cclet.2024.110802 shu

Current advances in nanomedicine-based therapies for acute kidney injury

English

Current advances in nanomedicine-based therapies for acute kidney injury

a.
Department of Hematology and Institute of Hematology and Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
b.
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China
c.
School of Pharmacy, Shanxi Medical University, Taiyuan 030001, China
d.
Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China
e.
Shanxi Provincial Key Laboratory of Drug Synthesis and Novel Pharmaceutical Preparation Technology, Shanxi Medical University, Taiyuan 030001, China
f.
Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
^* Corresponding authors.
E-mail addresses: chubingyang@126.com (B. Chu)
anderson-qian@163.com (Z. Qian).
¹ These authors contributed equally to the work.
Received Date: 12 November 2024
Accepted Date: 25 December 2024
Revised Date: 24 December 2024
Available Online: 15 October 2025

Abstract: Acute kidney injury (AKI) is a prevalent clinical syndrome characterized by a rapid loss of renal filtration function, with high incidence and mortality rates that are steadily rising. AKI not only affects the short-term prognosis of patients but also considerably raises the risk of progression to chronic kidney disease and end-stage renal disease, making it a significant threat to human health. Nanomedicine offers innovative therapeutic strategies for AKI and shows considerable potential in its treatment. This review comprehensively summarizes the application of nanomedicines in AKI therapy, with a particular focus on recent advances in the development of antioxidant, anti-inflammatory, and combined nanomedicine-based therapies targeting oxidative stress and inflammation, two primary pathological features of AKI. Additionally, this review also summarizes recent progress in AKI model construction to facilitate a better understanding and investigation of AKI. Overall, the review provides insights into innovative nanomedicine application in the effective treatment of AKI, hoping to provide new ideas for the clinical treatment of AKI.

Key words:

1. Introduction

Acute kidney injury (AKI) is a common clinical syndrome characterized by a dramatic decline in renal function and glomerular filtration rate, accompanied by decreased urine output (6-h urine volume < 0.5 mL kg⁻¹ h⁻¹), and/or increased serum creatinine concentration (0.3 mg/dL or ≥ within 48 h ≥ 1.5 times baseline) and urea nitrogen [1-3]. Clinically, AKI poses a significant challenge due to its high morbidity and mortality rates, necessitating accurate diagnosis and vigilant monitoring of renal dysfunction. However, there are no effective pharmaceuticals for AKI treatment. Traditional biomarkers like serum creatinine and urea nitrogen remain the primary tools for assessing renal function, but their specificity is limited. Novel biomarkers, including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, urinary α1/β2-microglobulin, and tissue inhibitor of metalloproteinases-2, offer improved insights into renal injury and stress [4-7]. Comprehensive evaluation using multiple biomarkers is essential for accurate diagnosis and prognosis. Given that AKI frequently progresses to chronic kidney disease (CKD), timely intervention following diagnosis is critical to improving patient outcomes.

The cause of AKI are diverse including sepsis, trauma, surgery, and exposure to nephrotoxic drugs. Current clinical management primarily aims to maintain or restore renal hemodynamics, prevent hypovolemia, and ensure adequate renal perfusion. Therapeutic strategies involve rehydration, correction of electrolyte imbalances, and avoidance of nephrotoxic agents or contrast agent [8]. However, these approaches can improve renal function but failed to achieve complete recovery. The pathological mechanisms underlying AKI are complex and multifaceted. Oxidative stress and inflammatory responses play pivotal roles in the progression of AKI. Small-molecule antioxidants, such as N-acetylcysteine (NAC), amifostine, and L-carnitine, have shown potential for AKI treatment [9,10]. However, their low renal targeting and limited efficacy have hindered clinical application, leaving an urgent need for safer and more effective therapeutic options to address AKI. Nanotechnology offers a promising solution and is expected to be a new strategy for managing AKI. Nanomedicine provides unique advantages over traditional drugs, including improved solubility, enhanced absorption, and improved distribution, while minimizing adverse effects and toxicity [11-14]. In recent years, nanomedicine-based therapies have shown significant promise in the management of AKI, which primarily focus on mitigating oxidative stress, reducing inflammation, and leveraging synergistic antioxidant and anti-inflammatory effects [15-18]. However, numerous challenges remain, necessitating further research and exploration to translate these therapies into clinical practice.

In addition, mouse models play an important role in the study of pathophysiological mechanisms and the evaluation of therapeutic effect. They are widely employed to simulate various etiologies and pathological processes by inducing kidney injury through methods such as ischemia-reperfusion (IR), nephrotoxic drug administration, infection, and other approaches. They serve as a critical foundation for studying AKI pathogenesis and evaluating therapeutic strategies.

In this review, we first introduce the primary pathological mechanisms of AKI. Subsequently, the common experimental models of AKI were presented. Moreover, the application of nanomedicine-based therapies for AKI were summarized. Finally, we discuss the potential challenges and prospects for the clinical application, hoping to provide new ideas for the management of AKI (Scheme 1).

Scheme 1

Scheme 1. Schematic diagram of pathology and mouse models of AKI, and nanomedicine-based therapeutic strategies for AKI. Created with Biorender.com.

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2. Pathology of AKI

The pathological mechanisms underlying AKI encompass a range of complex biological processes, including oxidative stress, inflammatory responses, apoptosis, necrosis, and cell cycle arrest [19,20]. Among these, oxidative stress and inflammation are recognized as pivotal contributors. In this section, we will focus on the role of oxidative stress and inflammation in the occurrence and progression of AKI.

2.1 Oxidative stress

Oxidative stress refers to a metabolic imbalance arising from excessive production of reactive oxygen species (ROS) that overwhelms the body's endogenous antioxidant defenses. This imbalance leads to the irreversible damage of critical biomolecules, including DNA, RNA, lipids, and proteins. The changes in ROS and related enzymes can be found in Section 1.1 (Supporting information). Oxidative stress is a key pathological factor in the development of AKI. Under normal physiological conditions, moderate oxidative stress helps maintain redox homeostasis and physiological functions. However, excessive or prolonged oxidative stress disrupts this balance, causing lipid peroxidation and vascular dysfunction, which in turn exacerbate inflammatory responses and ultimately result in renal cell death [21,22]. Mitochondria are the primary source of intracellular ROS. The kidney's proximal tubules, which are rich in mitochondria, are particularly susceptible to oxidative stress-induced injury [23]. During AKI, the clearance of mitochondrial ROS in renal tubules is impaired, leading to ROS accumulation (Fig. 1a). Elevated ROS levels cause mitochondrial dysfunction, lipid peroxidation, and oxidative damage to cell membranes, DNA, and proteins in renal tubular epithelial cells, further aggravating renal injury [24].

Figure 1

Figure 1. (a) Schematic illustration of pathophysiological processes of mitochondrial dysfunction. Copied with permission [23]. Copyright 2021, The Authors. (b) Inflammatory response signaling pathway in AKI. Copied with permission [26]. Copyright 2023, The Author(s).

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2.2 Inflammation

Inflammation is a protective response by the body to eliminate harmful pathogens and facilitate tissue repair following injury. However, excessive or dysregulated inflammation disrupts homeostasis, contributing to tissue damage, autoimmune diseases, and fibrosis. One of the main causes of AKI is an immune system-mediated inflammatory response [25]. During the early stages of AKI, damage to renal tubular epithelial cells is severe, accompanied by pronounced infiltration of immune-inflammatory cells. The signaling pathways involved in inflammation activation can be referenced in Section 1.2 (Supporting information). This is followed by the release of large quantities of pro-inflammatory cytokines, chemokines, and ROS, which exacerbate cellular and tissue injury (Fig. 1b). Molecules released from necrotic tubular cells, such as high-mobility group box 1, histones, heat shock proteins, fibronectin, and biglycan, enter the extracellular space, attracting additional inflammatory cells and further amplifying the inflammatory cascade [26]. The inflammatory processes in AKI involve both the innate and adaptive immune systems. Key cells of the innate immune response include natural killer cells, neutrophils, dendritic cells, and monocytes, which play critical roles in initiating and sustaining inflammation [27]. The changes in inflammatory cells can be found in Section 1.3 (Supporting information).

2.3 Crosstalk between oxidative stress and inflammation

During AKI, oxidative stress and inflammation are closely interconnected, forming a vicious cycle in which oxidative stress amplifies inflammatory responses, and inflammation-induced cellular damage further exacerbates oxidative stress [28]. Excessive production and release of ROS result in mitochondrial dysfunction, characterized by altered outer membrane permeability. This mitochondrial compromise leads to elevated ROS levels, further intensifying oxidative stress and initiating processes such as apoptosis, necrosis, and the release of pro-inflammatory factors, including tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-8, IL-1β and transforming growth factor β. These cytokines and chemokines are critical in activating leukocytes and exacerbating inflammatory injury.

Inflammatory damage disrupts the renal tubulointerstitial structure and impairs microvascular endothelial function, resulting in increased vascular permeability [29]. Additionally, interactions between damaged microvascular endothelial cells and activated leukocytes, mediated by adhesion molecules, further amplify the inflammatory cascade. The activation of inflammatory effector cells releases an abundance of inflammatory mediators, which exacerbate damage to renal tubular epithelial cells [29]. During the inflammatory process of AKI, phagocytes activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which facilitates ROS production to eliminate intracellular pathogens. However, excessive activation of NADPH oxidase leads to an overproduction of ROS, triggering oxidative stress. This establishes a vicious cycle between oxidative stress and inflammation, ultimately exacerbating renal dysfunction.

3. Experimental model of AKI

To advance the study of AKI, various animal models have been developed, with mice being the most commonly used experimental organisms for AKI research [30]. Establishing appropriate AKI animal models is essential for investigating the underlying pathological mechanisms and identifying potential therapeutic targets. Currently, three primary types of AKI models are used: IR, drug-induced, and infection-induced [30]. When selecting a mouse model of AKI, researchers need to consider it comprehensively according to the research purpose and experimental conditions. The successful construction of the model is typically assessed through the measurement of renal function indices such as serum creatinine, blood urea nitrogen and histopathological changes in the kidney. In this section, we will discuss the different methods for constructing AKI model.

3.1 IR AKI

The IR-AKI model, a classic model of hypoxic renal tubular injury, is among the most widely utilized in the study of AKI mechanisms and therapies. Due to the kidney's rich microvascular network, ischemia disrupts microcirculation and induces tissue damage. Subsequent blood reperfusion triggers a cascade of pathological processes, including severe inflammation, oxidative stress, and apoptosis, which exacerbate renal injury [31].

Currently, most mouse IR models are established by clamping the renal pedicles, which include the arteries and veins. These models can be categorized into bilateral IR, unilateral IR, and unilateral IR combined with contralateral nephrectomy. The severity of kidney injury varies depending on the site and method of occlusion. Owji et al. [32] demonstrated that clamping the renal arteries, veins, or the renal pedicle produces distinct pathological outcomes, with the severity of histological damage ranked as follows: vein > pedicle > artery (Fig. 2a). Vein clamping causes high arterial pressure to be transmitted to the renal microvasculature, leading to capillary wall rupture, hemorrhage, and subsequent vascular congestion upon reperfusion. This process creates a non-reflux zone in the kidney, resulting in more severe oxidative stress and vascular injury. In contrast, clamping the renal artery allows for retrograde venous blood flow into the kidney, leading to comparatively milder renal dysfunction. The duration of occlusion also significantly impacts the extent of kidney injury. Prolonged ischemic times result in more severe damage, and excessive durations can cause mortality in mice, rendering the model ineffective. Typically, occlusion times are set between 30 min and 45 min. Studies have reported that a 45-min ischemic duration in mice effectively replicates the hemodynamic changes observed in human ischemia-reperfusion injury [33-35]. The procedural details for ischemia-reperfusion AKI models can be found in Section 2.1 (Supporting information).

Figure 2

Figure 2. (a) Animal models for IR-AKI. Copied with permission [32]. Copyright 2018, The Authors. (b) Overview of the pathophysiological events in cisplatin nephrotoxicity. Copied with permission [39]. Copyright 2008, International Society of Nephrology.

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The bilateral IR model is the most commonly used for studying AKI and is particularly suitable for short-term efficacy evaluations. In contrast, the unilateral IR model offers distinct advantages, including more consistent results and lower mortality rates, making it more appropriate for long-term AKI research [36,37]. However, due to the compensatory effects of the contralateral healthy kidney, renal function indices may not accurately reflect the extent of damage in the affected kidney, and monitoring pathological changes in vitro remains challenging. The unilateral renal IR model combined with contralateral nephrectomy represents an optimization of the bilateral renal pedicle clamping model. This approach more effectively simulates the clinical immune-inflammatory damage associated with trauma and kidney transplantation. Compared to the bilateral IR model, it induces more significant pathological injury, closely resembling clinical conditions. However, this method involves the surgical removal of one kidney, necessitating advanced surgical skills and dynamic postoperative monitoring of the mice.

3.2 Drug-induced AKI

Drug-induced AKI is a widely used experimental model, as the glomerular, tubular, and interstitial cells in the kidney are particularly susceptible to damage by drugs or their metabolic products. The mechanisms of drug-induced AKI are generally classified into three categories: tubular injury, acute interstitial nephritis, and crystal nephropathy [38]. Tubular injury typically precedes AKI and is closely associated with the actions of transport proteins on the basolateral membrane. These proteins actively transport drugs to the proximal tubule, where they are secreted into the tubular lumen. This process can inhibit mitochondrial DNA polymerase activity, alter mitochondrial structure, and induce mitochondrial apoptosis, ultimately leading to AKI. Drugs commonly implicated include vancomycin, aminoglycoside antibiotics, sulfonamides, amphotericin, cyclosporine, cisplatin, ifosfamide, and contrast agents. Cisplatin-induced AKI is characterized by prominent tubular interstitial injury with necrosis in both proximal and distal tubules (Fig. 2b). The pathogenesis predominantly involves the metabolic activation of cisplatin, resulting in the generation of highly reactive species, disruption of the antioxidant defense system, and induction of inflammatory mediators, which collectively trigger endoplasmic reticulum stress and cell death [39]. Acute interstitial nephritis is an immune-mediated renal injury, histologically marked by inflammatory cell infiltration in the renal interstitium [40]. Common causative drugs include antibiotics, proton pump inhibitors, and nonsteroidal anti-inflammatory drugs. Crystal nephropathy is characterized by the deposition of crystals in the tubules [41]. Commonly implicated drugs include methotrexate and ethylene glycol. Currently, the most frequently used drug-induced AKI models involve cisplatin, glycerol, and contrast agents. Researchers can select appropriate models based on specific clinical problems or drugs of interest. The procedural details for drug-induced AKI models can be found in Section 2.2 (Supporting information).

3.3 Infectious AKI

Severe infection and septic shock are common causes of AKI, with sepsis-mediated systemic inflammatory responses being the primary representative [42]. The infectious AKI model is primarily used to study sepsis. Pathogenesis involves pathogens entering the bloodstream, directly or indirectly activating the endothelial system, and triggering systemic inflammation. This leads to endothelial cell apoptosis, increased vascular permeability, fluid and protein leakage, hypovolemia, hypotension, and reduced oxygen delivery. Simultaneously, stimulation of the renal inner cortex induces a significant release of nitric oxide (NO), which reduces vascular tone and contributes to abnormal coagulation, myocardial injury, tissue hypoperfusion, and oxygenation disorders [43,44]. Current methods for constructing infectious AKI models include endotoxin induction and surgical induction. The procedural details for infectious AKI models can be found in Section 2.3 (Supporting information).

Lipopolysaccharide (LPS), a Gram-negative bacterial cell wall component, is commonly used as an endotoxin to induce septic kidney injury. Once introduced into the organism, LPS promotes the release of pro-inflammatory factors, triggering immune-inflammatory responses [42]. The LPS-induced AKI model is simple, reproducible, and well-standardized. However, it has a narrow effective dose range, requiring strict regulation.

Cecal ligation and perforation (CLP) is another widely used method for septic AKI modeling. Unlike LPS-induced AKI, which is less representative of clinical conditions, the CLP model better simulates the localized nature and progression of clinical sepsis [45]. While the CLP method is straightforward and cost-effective, inconsistent surgical techniques can lead to varying degrees of infection and high animal loss, posing challenges for reproducibility and experimental reliability.

4. Nanomedicine-based therapeutic strategies

Nanotechnology-based therapeutic strategies are promising approaches for the management of AKI. Owing to its unique size and diverse surface modifications, it is possible to deliver therapeutic drugs to the site of kidney injury, thereby reducing off-target effects, preventing premature degradation of the drug, and improving the circulating half-life of the drug [46-49]. Nanomedicines with different physicochemical properties will affect their in vivo behaviors. Due to the glomerular filtration barrier, nanomedicines with particle sizes smaller than 10 nm are more likely to be absorbed by the kidneys [50]. But larger size nanoparticles are also allowed to accumulate in the kidney due to the damaged glomerular structure during AKI [51]. Nanoparticles with a particle size smaller than 5.5 nm can be excreted from the body through renal clearance. While the size of most reported therapeutic nanomedicines are 30–150 nm and are difficult to eliminate via urinary excretion, unless degraded to smaller sized particles or excretion through feces [52-55]. Nanoparticles with fluid dynamics up to 5.5 nm in diameter can be eliminated via the glomerulus. Some 12–16 nm nanoparticles can also be cleared out of the body through the kidney, possibly due to their chemical composition and size distribution profiles [55].

The surface composition of nanoparticles also can affect the distribution of nanoparticles. Nanoparticles modified by polyethylene glycol (PEG) can improve circulation time and biocompatibility, and reduce toxic side effects. Nanoparticles modified with targeting peptides such as mitochondria-targeting peptide SS-31 [56], potent renal tubule-target modifier L-serine [57], kidney targeting peptide (KTP) [58] or specific receptors such as anti-KIM-1 antibody [59], can reduce off-target effects, enhance their distribution at AKI sites and then improve therapeutic efficacy. Some nanoparticles with pathological microenvironment-responsive properties including ROS-responsive are also developed to enable them to precisely control drug release and improve drug efficacy [58,60-63]. Therefore, the management of AKI utilizing nanomedicine shows great potential.

At present, nanomedicine-based therapies for AKI mainly focus on reducing oxidative stress, alleviating inflammatory responses, and achieving synergistic antioxidant and anti-inflammatory effects. Here, we will discuss their recent advances.

4.1 Antioxidant therapy

ROS is closely related to the occurrence and progression of AKI [64-66]. Effectively scavenging ROS can mitigate inflammation and oxidative stress, thereby reversing AKI progression [67]. Nanomedicines with antioxidant activity have been developed for AKI therapy. According to their physio-chemical properties, it can be categorized into nanozymes, DNA origami, nanoparticles carrying antioxidants.

4.1.1   Nanozymes

Nanozymes, first proposed by Scrimin and coworkers in 2004 [68], are a kind of nanomaterials with enzyme catalytic activity [69-71]. Natural antioxidant enzymes are usually unstable, making them difficult to use for the treatment of AKI. The synthetic nanozymes have the advantages of good and adjustable catalytic activity, high stability and scale-up preparation, showing significant application potential in biomedical fields [72,73]. The most notable feature of nanozymes is that they can simultaneously display a variety of mimetic multienzyme activities, including superoxide dismutase (SOD), catalase (CAT), peroxidase and glutathione peroxidase (GPx), converting toxic ROS into non-toxic substances [74-76]. They have been used for the treatment of AKI. According to the composition, it could be divided into metal nanozymes and metal-polyphenol nanozymes.

(1) Metal nanozymes

Metal-based nanomaterials possess unique physical, chemical, and biological properties [70,77,78], making them highly promising for applications in drug delivery, biological imaging, and disease therapy [79]. At present, metal nanozymes such as cerium oxide (CeO₂) [80], iridium [81], CaPB [82], Prussian blue [83], RuO₂ [84] and Pt_5.65S [85] have been exploited for ameliorating AKI. CeO₂ nanozymes have been studied extensively. The enzyme mimetic activity of CeO₂ nanozymes is mainly caused by the dynamic balance between Ce⁴⁺ and Ce³⁺. When the ratio of Ce³⁺/Ce⁴⁺ is high, CeO₂ exhibits SOD-like activity: O₂^•− + Ce³⁺ + 2H⁺→H₂O₂ + Ce⁴⁺; O₂^•− + Ce⁴⁺→O₂ + Ce³⁺; on the contrary, CAT enzyme activity is displayed: 2Ce⁴⁺ + H₂O₂→Ce³⁺ + O₂ + 2H⁺ [86]. CeO₂ also exhibits significant free radical scavenging capacities against multiple free radicals including ^•OH, ^•NO and ONOO⁻ [87]. As a result, CeO₂ nanozymes have bright prospects for the treatment of AKI. Weng et al. [80] synthesized CeO₂ nanoparticles (CNPs) modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG₂₀₀₀) to alleviate cisplatin-induced AKI without interfering with the effects of platinum chemotherapeutic therapy (Figs. 3a and b). The ability of CNPs to catalyze the decomposition of H₂O₂ was substantially higher under neutral conditions than under acidic conditions. This pH selective antioxidant effect could alleviate AKI induced by chemotherapeutic agents without affecting the efficacy of the chemotherapeutic agents because the pH of the tumor microenvironment (pH 6.0–6.6) is distinctly different from that of the kidney (pH 7.4). Furthermore, CNPs showed obvious renal protection in mice with cyclophosphamide induced AKI. Gao et al. [88] designed a PEG-modified based on black phosphorus (BP)/ceria catalytic tunable nanozymes (BP@CeO₂-PEG) with strong pH selectivity. Under neutral conditions (pH 7.4), BP and Ce⁴⁺ undergo redox reaction to generate Ce³⁺ and PO₄³⁻, and PO₄³⁻ will promote the generation of ATP, accelerate the catalytic oxidation cycle, and remove ROS in a sustainable and effective manner; whereas, at acidic (pH 6.6), the excess H⁺ discourages Ce⁴⁺ from being converted to Ce³⁺, which prevents the re-exposure of the active site and blocks the antioxidative cycle. Jiang et al. [85] reported an ultra-small platinum-based pre-nanozyme (Pt_5.65S). Due to its small size (4 nm), it preferentially accumulates in the kidney and can be effectively cleared. This enzyme has low enzyme activity in neutral conditions, but can be activated in acidic and inflammatory environments to exert CAT and SOD activities and release hydrogen sulfide gas to facilitate the expression of antioxidant molecules and enzymes. Thereby, it can effectively relieve cisplatin and IR-AKI through the synergistic effect of hydrogen sulfide and nanozymes.

Figure 3

Figure 3. (a) Schematic illustration of catalytic activity tunable CeO₂ nanoparticles with context-dependent cytoprotective activities for AKI prevention during chemotherapy. (b) The catalytic enzyme activities of CeO₂ nanoparticles at different pH conditions (pH 7.4 and 6.0). Copied with permission [80]. Copyright 2021, The Author(s). (c) The synthesis of RosA-Mn nanoparticles. Copied with permission [91]. Copyright 2023, American Chemical Society. (d) tFNAs as a therapeutic drug for glycerol-induced AKI. Copied with permission [103]. Copyright 2021, Elsevier B.V.

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Although metal nanozymes exhibit excellent biocompatibility, their long-term or large-scale application may pose potential toxicity risks, as the accumulation of metal elements in the body could adversely affect human health. Therefore, strict dosage control is essential when using metal nanozymes for AKI treatment. Additionally, the cost of metal nanozymes should be considered as a factor in their clinical application [89]. Future research should focus on further elucidating their therapeutic mechanisms, optimizing nanozyme design and modification strategies, and developing more effective treatment protocols to enhance the safety and efficacy of metal nanozymes in AKI therapy.

(2) Metal polyphenol nanozymes

Natural polyphenols such as curcumin (Cur), quercetin (Que), gallic acid (GA), and rosmarinic acid (RosA) have garnered significant attention due to their potent antioxidant properties and excellent biocompatibility. However, their biological applications are limited by low water solubility and poor bioavailability [90]. In recent years, studies have reported that these polyphenols can chelate with metal ions to form nanoparticles, which have demonstrated promising renal accumulation and ROS-scavenging activity for the treatment of AKI [91]. These metal polyphenol nanozymes includes complexes such as Fe³⁺ with Cur [92], glutathione [93,94] or GA [95], Mn²⁺ with RosA [91], and RuPt with Cur [96].

Zhang et al. [92] developed several ultra-small (< 10 nm) metal polyphenol nanodots, in which Fe-Cur nanodots excellent antioxidant properties and high renal uptake and significantly improved renal function in glycerol-induced AKI mice. Yuan et al. [91] synthesized RosA-Mn nanoparticles (about 142 nm) using RosA and Mn²⁺, which could effectively target renal tubules, reduce tubular cell apoptosis (Fig. 3c). These nanoparticles also exhibited a multi-enzyme cascade ability to eliminate free radicals, thereby restoring renal function in cisplatin-induced AKI mice. Pan et al. [96] designed a bimetal nanozyme combined with Que to treat AKI. Initially, Pt was combined with other metals such as Ru, Mn, Fe, Cu, Ni, Zn, and Au to synthesize bimetallic nanozymes. Among these, RuPt nanozymes showed superior free radical scavenging efficacy. After coordinating with Que, it exhibited enhanced antioxidant activity, particularly against 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, as well as significantly improved anti-apoptotic effects. In both glycerol- and cisplatin-induced AKI mouse models, it effectively reduced oxidative stress and provided therapeutic benefits for AKI.

4.1.2   DNA origami

In recent years, significant progress in DNA nanotechnology has enabled the creation of highly programmable DNA origami with exceptional precision and complexity, making them ideal precision nanomaterials [97,98]. As the genetic material in living organisms, DNA offers excellent biocompatibility and biodegradability, providing advantages for nanomedicine applications [99,100]. Notably, the abundance of nucleophilic groups in DNA allows it to bind electrophilic ROS, enabling the removal of harmful ROS in the body. Additionally, DNA nanostructures exhibit low immunogenicity and good biocompatibility, making them promising antioxidants [101].

Jiang et al. [102] developed three distinct DNA origami nanostructures (DON): rectangular (rec-DON), triangular (tri-DON), and tubular (tub-DON). Among these, rec-DON demonstrated significant kidney-protective effects, comparable to the conventional antioxidant NAC, effectively scavenging free radicals and mitigating renal damage. Zhang et al. [103] reported that tetrahedral framework nucleic acids (tFNAs) remained stable for over 9 h in DNase-rich cell lysates, and exhibited strong kidney-targeting properties (Fig. 3d). By reducing oxidative stress and inhibiting apoptosis, tFNAs successfully restored renal function in glycerol-induced AKI mice. DNA origami combined with imaging probes offers both diagnostic and therapeutic potential for AKI. Xu et al. [99] developed a microRNA-responsive nanoantenna composed of gold nanorods (AuNRs) linked by rectangular DON (rDONs), with surface plasmon resonance in the near-infrared Ⅱ (NIR-Ⅱ) window (~1060 nm) for deep tissue photoacoustic imaging. The nanoantenna exhibits renal targeting and retention, showing reduced PA signals in AKI mice due to AuNRs detachment upon miR-21 interaction. The bare rDONs scaffold traps more ROS (1.5 times higher than rDONs@AuNR dimer), alleviating IR-AKI. The nanoantenna detects AKI onset within 10 minutes, outperforming conventional methods, while also improving renal function, offering a novel approach for early AKI diagnosis and treatment.

4.1.3   Nanoparticles delivering antioxidants

Nanoparticle-mediated delivery of antioxidants is also a common strategy for treating AKI. It can enhance the in vivo distribution and bioavailability and reduce side effects [104,105]. Depending on the carrier, they can be categorized as protein nanoparticles, polymer nanoparticles and other nanoparticles.

(1) Protein nanoparticles

The cavities inside the ferritin nanocages can be used as carriers for delivering drugs. Lou et al. [106] developed ferritin nanocages loaded with curcumin (FNC/Cur), which specifically targeted injured kidneys within 4 h. These nanocages were internalized by renal tubular epithelial cells via transferrin receptor-1 (TfR1) and released Cur in the acidic, proteolytic lysosomal environment. Cur exerted antioxidant effects, while depolymerized FNC bound to lysosomal redox-activated iron, reducing iron-mediated oxidation. The synergistic action of FNC and Cur effectively reversed IR-AKI. Xin et al. [107] designed a novel TAT-MKK3b peptide nanoparticles that the linked mitogen-activated protein kinase 3b (MKK3b) with the cell-penetrating TAT sequence self-assembled to form well-ordered nanostructures (TMNPs) via tyrosinase oxidation. These peptide nanoparticles exhibited renal tubular epithelial cell targeting ability and specifically inhibition effect of p38. They also could inhibit ferroptosis by clearing ROS and activating the solute carrier family 7 member 11 (SLC7A11)/GPx4 signaling pathway, thus treating AKI or preventing its progression to CKD.

(2) Polymer nanoparticles

Polymeric nanocarriers are considered as ideal drug delivery materials due to their physicochemical properties such as biodegradability, biocompatibility, water solubility and storage stability [108]. Polymer nanoparticles delivering antioxidants have been developed, such as PVP-modified Cur nanoparticles [109], green nanoparticles [110], and nanoparticles delivering vitamin E [111], rutin [112], irisin [113] and rapamycin (Rapa) [114]. In addition, modification of targeting ligands or camouflage with cell membranes can enhance the enrichment of nanomedicine at AKI.

Liu et al. [61] developed nanoparticles comprising the mitochondria-targeting antioxidant peptide SS-31, anionic hyaluronic acid (HA), and cationic chitosan via electrostatic force. In AKI mice, HA specifically binds to the overexpressed CD44 receptor to improve the targeting ability. In the lysosomal acidic environment, nanoparticles degraded to release SS-31, which preserved mitochondrial integrity, scavenged excess ROS. Thereby, it alleviated renal injury in AKI mice. Yao et al. [56] designed a theranostic nano-platform, PISP, based on indocyanine green and SS-31-loaded poly(lactic-co-glycolic acid) (PLGA) coated with a platelet membrane. The natural aggregation of platelets at vascular injury sites enabled effective kidney targeting. PISP demonstrated strong antioxidant activity, alleviated mitochondrial damage, and treated glycerol-induced AKI. Moreover, indocyanine green enabled near-infrared imaging, allowing real-time monitoring of PISP distribution.

Zhang et al. [58] developed nanoparticles with yolk-shell structure, in which KTP-targeting peptide was modified on the liposome-PEG-PLGA hybrid nanoparticles. KTP enabled these nanoparticles effective kidney targeting. In slightly acidic inflammatory environments, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM) was released from nanoparticles, which is subsequently depolymerized by cellular lactase to BAPTA. BAPTA chelates excess intracellular Ca²⁺, breaking the feedback loop between Ca²⁺ and ROS at its source. This mechanism significantly reduces apoptosis and restores renal function, offering a promising strategy for AKI treatment.

(3) Others

Some inorganic nanoparticles loaded with antioxidants have also been developed for the treatment of AKI. Zhang et al. [113] developed macrophage membrane-cloaked irisin-loaded metal-organic frameworks (MOF) nanoparticles, which avoided phagocytosis and targeted inflammatory injury sites, extending irisin's half-life from less than 1 h to 7.4 h. Besides accumulation in kidney mitochondria, MCM@MOF@irisin also partially accumulated in the injured liver and lungs, demonstrating protective effects against injury in these organs. Wang et al. [114] developed Rapa-loaded hollow mesoporous Prussian blue (HMPB) nanoparticles modified with HA to produce HA-HMPB-Rapa, which could actively target to the damaged renal tubular via HA-CD44 axis. HMPB scavenged excessive ROS, while Rapa-induced mitophagy removed damaged mitochondria. Through these dual effects in mitigating oxidative stress, good therapeutic efficacy was achieved in IR-AKI model.

4.2 Anti-inflammatory therapy

Inflammation is the main pathological feature of AKI, and inhibiting the inflammatory response is a key therapeutic strategy for AKI [115-118]. The current use of nanomedicines to inhibit the inflammatory response provides new ideas and approaches for the treatment of AKI, which is categorized into several mechanisms, including direct inhibition of inflammatory cytokine production, reduction of apoptosis, and iron-supplementation therapy [116].

4.2.1   Anti-inflammatory substances-loaded nanomedicines

Delivery of anti-inflammatory substances using nanoparticles is able to realize precise treatment, thus improving the therapeutic effect and reducing side effects. According to the properties, anti-inflammatory substances can be divided into small molecule drugs and factors.

(1) Delivery of anti-inflammatory small molecule drugs

Inflammatory kidney diseases are commonly treated with high doses of glucocorticoids (GCs). GCs can bind to the glucocorticoid receptor, then the activated glucocorticoid receptor interacts with glucocorticoid-responsive elements on anti-inflammatory genes or pro-inflammatory transcription factors, ultimately suppressing the expression of pro-inflammatory factors and exerting anti-inflammatory effects [119,120]. Although effective in controlling inflammation, prolonged high-dose GCs therapy can lead to severe side effects [121]. To address this, glucocorticoids-loaded nanomedicines have been developed, such as PEG-coated liposomes loaded with prednisone [122] and sialic acid (SA)-modified calcium phosphate gel-lipid nanoparticles encapsulating dexamethasone [123]. Beyond glucocorticoids, other drugs including resveratrol [59], disulfiram [124] and selenium [125] loaded nanoparticles have also been explored for AKI treatment.

Liu et al. [123] developed SA-NPs based on SA-modified 1,2-dioleoyl-sn-glycero3-phosphate monosodium salt (DOPA) for delivering dexamethasone sodium phosphate (DSP). SA-NPs could bind to the overexpressed E-selectin receptors, significantly improving targeting efficiency and retention time. Compared to free DSP, SA-NPs demonstrated reduced clearance, and effectively downregulated pro-inflammatory factors such as TNF-α and IL-6. They also scavenged free radicals, reduced apoptosis, and alleviated IR-AKI.

Resveratrol, a non-flavonoidal polyphenolic compound, exhibits anti-inflammatory effects via multiple pathways [126]. While Lin et al. [59] developed anti-KIM-1 antibody-conjugated PLGA nanoparticles loaded with resveratrol, which inhibited the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in mouse kidneys. These nanoparticles reduced IL-1β secretion, promoted renal autophagy, thereby mitigating inflammatory kidney damage. Guo et al. [124] designed bovine serum albumin (BSA) nanoparticles for disulfiram deliver. These nanoparticles showed enhanced accumulation and prolonged retention at sites of kidney injury. They reduced inflammation caused by pyroptosis and protected renal tubules by targeting gasdermin D protein.

Artesunate is one of the first-lines drugs for malaria, also showed anti-inflammatory and immune regulation effects. Zhang et al. [127] engineered artesunate-loaded liposomes modified with triphenylphosphine. These liposomes effectively targeted mitochondria to alleviate cisplatin-induced AKI by anti-inflammatory effects of artesunate.

(2) Delivery of anti-inflammatory factors

Anti-inflammatory factors can ameliorate the inflammatory reaction, but the poor stabilization in vivo limited their application. Delivery of them via nanocarriers can improve their in vivo physicochemical properties, thus improving therapeutic efficacy. Currently, nanoparticles have been used to deliver anti-inflammatory factors, such as Toll-like receptor 9 (TLR9) antagonist ODN2088 [117], IL-33 [128], IL-10 [129], TNF-α and hepatocyte growth factor [130], and nicotinamide adenine dinucleotide (NAD⁺) [131], for the treatment of AKI.

TLR9 is an important receptor expressed in immune system cells and can activate immune reactions. In AKI, TLR9 is significantly upregulated. Han et al. [117] synthesized PEG-PLGA nanoparticles loaded with the TLR9 antagonist ODN2088 to alleviate renal injury in IR-AKI mice. These nanoparticles selectively targeted renal tubular cells, reduced macrophage and neutrophil infiltration, and inhibited apoptosis, thereby achieving therapeutic efficacy. Fan et al. [129] encapsulated IL-10 in rDON nanoparticles to create IL-10@rDON, enhancing immunotherapy for promoting regeneration after IR injury. The in vivo studies showed comparable renal fluorescence signals in IR mice at 2 and 6 h post-intravenous administration of IL-10@rDON and IL-10 alone. However, at 12, 24, and 48 h, IL-10@rDON significantly enhanced IL-10 accumulation and retention in renal tissues. This suggests that DNA origami combined with anti-inflammatory factors offers a promising new approach for AKI immunotherapy.

Studies [132,133] have demonstrated a strong link between AKI progression and NAD⁺ depletion. Administering NAD⁺ or its precursors can attenuate AKI; however, the poor targeting, short half-life, and instability of NAD⁺ limit its therapeutic potential. To address these challenges, Duan et al. [131] used ultra-small Fe₃O₄ nanoparticles to deliver nicotinamide mononucleotide (NMN), an NAD⁺ precursor. NMN binds Fe₃O₄ nanoparticles via phosphate groups, mimicking nicotinamide riboside, and targets renal cells through nicotinamide riboside kinase 1 on the cell membrane, exerting anti-inflammatory effects (Fig. 4a). Mechanistic studies highlighted that timely iron supplementation following anti-inflammatory treatment plays a critical role in AKI recovery, suggesting a novel therapeutic strategy distinct from conventional antioxidant and anti-inflammatory approaches. Kong et al. [134] developed GA-NAD nanoparticles by conjugating NAD⁺ with GA and chelating it with Fe³⁺, which also showed improved therapeutic effects and inhibited the progression from AKI to CKD.

Figure 4

Figure 4. (a) Structural formation of NMN ligand on the surface of Fe₃O₄ nanoparticle. Copied with permission [131]. Copyright 2023, Wiley-VCH GmbH. (b) Schematic illustration of the preparation of MnCO@hMSN@NM-PS nanomedicine and its treatment for AKI in a rat model by the release of CO from MnCO@hMSN@NM-PS in the presence of H₂O₂ in renal tubular epithelial cells. Copied with permission [157]. Copyright 2022, American Chemical Society.

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4.2.2   Cell derivative-based therapy

Stem cells are a class of undifferentiated cells with the potential for self-renewal, proliferation and multidirectional differentiation, and have been regarded as ideal "seed" cells for repairing tissue damage [135]. Stem cell therapy has emerged as a very promising approach for treating AKI. However, clinical application is limited by challenges such as low in vivo survival rates and cellular senescence [136]. To overcome these limitations, extracellular vesicles (EVs) derived from stem cells and cell-mimicking nanoparticles have been regarded as effective alternatives for promoting renal repair [137-140].

(1) Exosomes

EVs secreted by mesenchymal stem cells (MSC) carries large amount of cargos such as mRNA and protein, are responsible for intercellular communication and maintaining physiological functions [141-143]. Among EVs, exosomes are an important subtype with unique molecular composition and biological activity, and show significant potential in drug delivery and therapy [144-146]. Hong et al. [115] reported that EVs derived from induced-MSC (iMSC-EVs) reduced levels of neutrophil gelatinase-associated lipocalin and TNF-α by inhibiting extracellular signal-regulated kinase 1/2 activation. These EVs also decreased macrophages and neutrophil infiltration. Kim et al. [147] demonstrated enhanced reno-protective effects by priming iMSCs with a pan-peroxisome proliferator-activated receptor (PPAR) agonist than iMSC-EVs. However, the short half-life of MSC-EVs and their rapid clearance in vivo remain challenges. To address this, Zhou et al. [148] developed a matrix metalloproteinase-2 (MMP2)-sensitive self-assembling peptide hydrogel for localized and sustained MSC-EV delivery, significantly reducing inflammation and inhibiting apoptosis. Huang et al. [149] genetically modified MSCs to express mutant β-galactosidase (β-GAL^H363A), enabling precise NO release from a novel cell membrane-anchored NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate. Systemic administration of these modified MSCs in an IR-AKI mouse model promoted NO release, enhancing stem cell-mediated tissue regeneration and therapeutic efficacy.

Beyond MSC, exosomes derived from adipose-derived mesenchymal stem cells (ADSCs-Exos) or fibroblastic reticular cell (FRC-Exos) also have been developed. Gao et al. [150] demonstrated that ADSCs-Exos protect renal function by regulating transcription factor nuclear factor kappa B (NF-κB) activity via sirtuin 1. He et al. [151] showed that ADSCs-Exos delivering circVMA21 alleviate LPS-induced AKI through miR-16–5p regulation. Li et al. [152] found that FRC-Exos enhanced renal function recovery in CLP-induced AKI. Compared with macrophage-derived exosomes, CD5 antigen-like (CD5L) was the most upregulated protein in FRC-Exos. Then, FRC-Exos enriched with CD5L protein via lentivirus transfection, were further modified with the renal tubular cell-targeting peptide LTH, promoting binding to injured renal tubular cells. CD5L degraded NLRP3 inflammasomes via phosphatase and tensin homologue induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy, improving renal function.

Macrophage-derived microvesicles have also been used to deliver anti-inflammatory agents such as dexamethasone [153] and IL-10 [154] for AKI therapy, effectively suppressing inflammation and fibrosis at renal injury sites.

(2) Cell-mimicking nanomedicines

Cell membrane-encapsulated nanoparticles consist of synthetic cores coated with natural cell membranes [155]. The abundance of membrane proteins on the cell membrane surface enables these nanoparticles to retain source cell-specific functionalities, such as self-recognition, immune system interaction, biotargeting, and localization to specific regions. These features enhance biocompatibility, reduce immunogenicity, facilitate immune evasion, extend circulation time, and improve targeting capabilities, making cell membrane biomimetic nanoparticles great promise for advancing nanomedicines in drug delivery [156]. Inflammatory cells including macrophages or neutrophils biomimetic nanoparticles have been developed as innovative strategies to modulate the inflammatory response and treat various inflammatory diseases effectively.

Zhou et al. [157] developed an nanomedicine (MnCO@hMSN@NM-PS), consisting of manganese carbonyl loaded into hollow mesoporous silica nanoparticles and coated with phosphatidylserine-modified neutrophil membranes (Fig. 4b). The biomimetic chemotaxis of the neutrophil membrane to the inflammation site and the active binding of phosphatidylserine to KIM-1 facilitates this nanomedicine accumulation in injured renal tubular cells. The locally released carbon monoxide exerts anti-inflammatory and oxidative stress-reducing properties, thus improving renal function. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is closely associated with inflammation in AKI [158]. Shen et al. [159] developed renal tubular epithelial cell membrane-coated PEG-PLGA nanoparticles loaded with the STING antagonist C176. These nanoparticles targeted renal tubules through αV integrin-mediated adhesion, effectively coordinating innate and adaptive immune responses to treat cisplatin- and IR-AKI. The STING antagonist alleviated inflammation by inhibiting the STNG-TANK binding kinase 1-interferon α (STING-TBK1-IFN-α) pathway, while also repolarizing macrophages to the M2 anti-inflammatory phenotype. Additionally, programmed death ligand 1 (PD-L1) on the nanoparticle surface blocked CD80 on dendritic cells, suppressing T-cell activation and promoting an anti-inflammatory adaptive immune response. Ma et al. [160] prepared N-MVs@IL-37 by extruding purified neutrophil membranes to avoid the side effects of natural EVs. These nanoparticles expressed P-selectin glycoprotein ligand 1 (PSGL1), a neutrophil membrane protein that facilitates endothelial cell binding, enabling efficient delivery of IL-37 to IR kidneys. The therapeutic effect of IL-37 was enhanced by inhibiting endothelial cell apoptosis, promoting endothelial cell proliferation and angiogenesis, and reducing inflammatory factor production and leukocyte infiltration, demonstrating significant efficacy in treating IR-AKI.

4.2.3   Gene therapy

In recent years, RNA interference (RNAi) technology has garnered significant attention and demonstrated potential as a therapeutic strategy for AKI [161,162]. While free siRNA exhibits natural renal tropism, its clinical application is limited by intrinsic challenges, including its large size, negative charge, and susceptibility to degradation [163,164]. Additionally, prolonged high-dose administration may cause off-target effects, inhibiting target genes in non-target tissues [165,166]. Thus, selecting an appropriate carrier for the specific delivery of siRNA is crucial.

Tumor-suppressor protein p53, a key mediator of apoptosis and inflammatory pathways, has been identified as a contributor to tubular injury in AKI. The chemokine receptor C-X-C chemokine receptor 4 (CXCR4) is overexpressed on the injured proximal tubule cells in AKI. Oupický group developed cationic polymers by the conjugation of α-cyclam-p-toluic acid (CPTA, a CXCR4 ligand) with inulin or chitosan to deliver siRNA targeting p53 [167,168]. These carriers exhibited enhanced accumulation in injured kidneys, reduced tubular cell death and renal injury, attenuated inflammation, and improved renal function. Additionally, they utilized a phenylene-cyclam derivative with hexamethylenebisacrylamide containing truncated AMD3100 (a CXCR4 antagonist) as a carrier for siRNA against p53, achieving synergistic therapeutic effects through combined CXCR4 inhibition and p53 gene silencing [169]. Arginase-2 is an inflammatory regulatory protein, involving IL-10 and oxidative stress. Gu et al. [170] synthesized a poly(spermidine) (PSPD) vector using spermidine (SPD) as a monomer. PSPD retains the anti-inflammatory, antioxidant, and autophagy-activating properties of SPD while exhibiting high siRNA condensation efficiency and strong loading capacity. By delivering arginase-2 siRNA, the system mitigates oxidative damage and enhances mitochondrial autophagy, thereby alleviating drug-induced AKI. Transcription factors P65 and Snai1 can drive inflammation and fibrosis. Tang et al. [171] designed RNAi therapeutics based on erythrocyte-derived EVs (REVs) for renal protection. By delivering P65 and Snai1 siRNAs to injured renal tubular cells via REVs functionalized with the KIM-1-binding LTHVVWL peptide, this approach effectively alleviated AKI induced by ischemia-reperfusion or unilateral ureteral obstruction.

4.3 The Combination of antioxidant and anti-inflammatory strategies

Given the complex pathological mechanisms of AKI, multi-target interventions are expected to enhance therapeutic efficacy. Nanomedicines have been developed to simultaneously scavenge ROS and suppress inflammatory responses, thereby improving AKI treatment outcomes [46,50,172]. This section focuses on combined therapeutic strategies based on different nanocarriers, specifically metallic nanoparticles and polymer nanoparticles.

4.3.1   Metal-based nanomedicines

Some metal-based nanoparticles inherently possess ROS-scavenging capabilities and inflammation suppression capacity. Zhang et al. [173] synthesized 1–2 nm gold nanozymes (Au NCs-NAC) using NAC as both an antioxidant and a capping agent. These nanozymes demonstrated enhanced targeting ability and prolonged retention, effectively scavenging ROS, reducing inflammatory factor expression (IL-6 and TNF-α), and improving renal function in a rhabdomyolysis-induced AKI mouse model (Fig. 5a). Other metallic nanoparticles such as cerium oxide nanoparticles [174] and serine-modified rhodium nanoparticles [175] also showed both multiple enzyme activities to reduce stress and anti-inflammatory effects. Some metal-based nanoparticles can also serve as delivery vehicles for anti-inflammatory agents, enabling synergistic therapeutic effects for AKI. Gu et al. [176] synthesized cerium-luteolin nanocomplexes with an average diameter of 60 nm via a one-pot method (Fig. 5b). Beyond antioxidant activity, luteolin also possesses anti-inflammatory properties, and can alleviate inflammation by regulating macrophage polarization and relieving inflammatory reactions. These nanocomplexes effectively scavenged excessive ROS, promoted macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, inhibited the NF-κB pathway, and reduced the release of inflammatory cytokines.

Figure 5

Figure 5. (a) Schematic illustration of broad-spectrum antioxidant and anti-inflammatory activities of ultrasmall Au NCs-NAC for AKI alleviation as compared with NAC. Copied with permission [173]. Copyright 2021, Ivyspring International Publisher. (b) Schematic illustration of the antioxidation activity of CeLutNCs. Copied with permission [176]. Copyright 2024, American Chemical Society.

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4.3.2   Polymer nanoparticles

Polymeric nanoparticles can achieve synergistic anti-inflammatory and antioxidant effects by delivering both antioxidant and anti-inflammatory agents, utilizing the intrinsic functional properties of polymers, or disguising their surfaces with cell membranes endowed with specific functions [177-179].

Numerous nanoparticles loaded with anti-inflammatory and antioxidant agents, such as Cur [184], Que [184], resveratrol [185], gambogic acid [186], and GA [187], have been developed for AKI treatment. Du et al. [180] constructed folic acid receptor-mediated nanomedicines by efficiently loading Cur and resveratrol (Res) in poloxamer F127/tocopheryl polyethylene glycol succinate (TPGS) nanoparticles with folic acid as the targeting moiety. This nanomedicine demonstrated the accumulation of Cur and Res in the kidney and the ability to safely and effectively treat cisplatin-induced AKI. Li et al. [181] synthesized PEG-modified gambogic acid nanoparticles by coupling hydrophobic gambogic acid with hydrophilic NH₂-PEG5000-NOTA, which effectively scavenged ROS, inhibited apoptosis, and reduced neutrophil and macrophage infiltration, alleviating renal injury induced by cisplatin and glycerol. Zhou et al. [182] developed SC@Se/GA nanoparticles consisting of GA and nano-selenium. Upon reaching the acidic intracellular environment, nanoparticles degrade to release GA and nano-selenium. Nano-selenium enhanced GPx activity to scavenge ROS, while GA inhibited inflammatory responses by reducing the expression of inflammatory factors, including IL-6 and TNF-α. Thus, SC@Se/GA nanoparticles exert synergistic anti-inflammatory and antioxidant effects, markedly alleviate cisplatin-induced AKI and restores renal function.

Melanin, an endogenous polymer, possesses intrinsic ROS scavenging capabilities. It has a high chelating capacity with metal ions and strong binding affinity with various aromatic structural drugs, and has been used as drug delivery carrier for AKI [183]. Sun et al. [183] developed a CD44-tagrted nanomedicines, in which dexamethasone was conjugated to melanin nanoparticles and then complexed with HA. Upon degradation of these nanoparticles, ultra-small melanin nanoparticles and dexamethasone were released. Melanin nanoparticles primarily exerted antioxidant effects, while dexamethasone served as an anti-inflammatory agent. This dual-action system effectively scavenged excess ROS, mitigated inflammatory responses, inhibited apoptosis, and restored mitochondrial structure and function, thereby demonstrating therapeutic efficacy against IR-AKI.

Huang et al. [184] developed a KTP-modified biomimetic nanoplatform based on renal tubular epithelial cell membrane-coated zeolite imidazolate framework-8 (ZIF-8) for the delivery of fibroblast growth factor 21 (FGF21). Through the dual targeting provided by renal cell membranes and KTP binding, this biomimetic nanoplatform efficiently delivered FGF21 to the damaged kidney, promoting the recovery of renal function through antioxidant and anti-inflammatory activities. Liu et al. [185] designed the antioxidant coenzyme Q10-loaded PEG-PLGA nanoparticles coated with neutrophil cell membranes. By leveraging the inflammation tropism of neutrophils, this nanomedicine enabled precise targeting to injured kidney. Antioxidant coenzyme Q10 stabilized the mitochondrial respiratory chain and mitigated mitochondrial damage in renal tubular epithelial cells, while neutrophil membrane neutralized pro-inflammatory cytokines to inhibit inflammatory response. Both works synergistically to protect kidney function.

5. Conclusion and future perspectives

AKI is a is a severe condition primarily driven by oxidative stress and inflammation. Eliminating ROS and suppressing inflammatory reactions are crucial therapeutic strategies. Over the past few decades, significant progress has been made in nanomedicine for AKI treatment. Antioxidant nanomedicines, anti-inflammatory nanomedicines, extracellular vesicles, cell-mimicking nanoparticles have shown great potential due to their ability to target the kidney effectively, enhance drug bioavailability, minimize side effects, and improve therapeutic effects. However, nanomedicines face several challenges in AKI. Most studies rely on rodent models, particularly mice, which differ significantly from humans with lower capillary and mitochondrial density, metabolic rate, and response to oxidative stress. These differences, along with the complexity of clinical AKI patients often presenting with multiple comorbidities, limit the translatability of findings [186,187]. More diverse animal models are needed for comprehensive efficacy assessments. Additionally, despite increasing research, no nanomedicines for AKI treatment have been clinically approved, as mechanisms observed in rodent studies may not fully replicate human pathophysiology. A deeper understanding of nanomedicine interactions at sites of renal injury is crucial. To accelerate clinical applications, nephrologists and researchers must focus on in vivo studies and clinical trials while addressing key challenges, including toxicity, long-term safety, biocompatibility, cost, stability, and controlled drug release. The successful clinical translation of nanomedicines for AKI requires interdisciplinary collaboration among experts in medicine, chemistry, cell biology, and nanotechnology.

In conclusion, we think that with the development of technology and continued efforts, nanomedicines are poised to offer transformative hope for AKI patients in the future.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

CRediT authorship contribution statement

Ruimiao Chang: Supervision, Funding acquisition, Conceptualization. Xinying Qu: Writing – review & editing, Writing – original draft, Investigation. Yuting Ye: Writing – original draft. Ying Qu: Supervision, Resources, Funding acquisition, Conceptualization. Bingyang Chu: Writing – review & editing, Supervision, Resources, Project administration, Investigation, Funding acquisition, Conceptualization. Zhiyong Qian: Validation, Supervision, Resources, Project administration, Funding acquisition, Conceptualization.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 82272147, 32271450, U21A20417, 31930067, 82472138, 32200323) and the Science and Technology Project of Sichuan Province (Nos. 2023YFS0118, 2024YFFK0322), the China Postdoctoral Science Foundation (No. 2023M732144).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110802.
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Scheme 1 Schematic diagram of pathology and mouse models of AKI, and nanomedicine-based therapeutic strategies for AKI. Created with Biorender.com.

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Figure 1 (a) Schematic illustration of pathophysiological processes of mitochondrial dysfunction. Copied with permission [23]. Copyright 2021, The Authors. (b) Inflammatory response signaling pathway in AKI. Copied with permission [26]. Copyright 2023, The Author(s).

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Figure 2 (a) Animal models for IR-AKI. Copied with permission [32]. Copyright 2018, The Authors. (b) Overview of the pathophysiological events in cisplatin nephrotoxicity. Copied with permission [39]. Copyright 2008, International Society of Nephrology.

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Figure 3 (a) Schematic illustration of catalytic activity tunable CeO₂ nanoparticles with context-dependent cytoprotective activities for AKI prevention during chemotherapy. (b) The catalytic enzyme activities of CeO₂ nanoparticles at different pH conditions (pH 7.4 and 6.0). Copied with permission [80]. Copyright 2021, The Author(s). (c) The synthesis of RosA-Mn nanoparticles. Copied with permission [91]. Copyright 2023, American Chemical Society. (d) tFNAs as a therapeutic drug for glycerol-induced AKI. Copied with permission [103]. Copyright 2021, Elsevier B.V.

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Figure 4 (a) Structural formation of NMN ligand on the surface of Fe₃O₄ nanoparticle. Copied with permission [131]. Copyright 2023, Wiley-VCH GmbH. (b) Schematic illustration of the preparation of MnCO@hMSN@NM-PS nanomedicine and its treatment for AKI in a rat model by the release of CO from MnCO@hMSN@NM-PS in the presence of H₂O₂ in renal tubular epithelial cells. Copied with permission [157]. Copyright 2022, American Chemical Society.

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Figure 5 (a) Schematic illustration of broad-spectrum antioxidant and anti-inflammatory activities of ultrasmall Au NCs-NAC for AKI alleviation as compared with NAC. Copied with permission [173]. Copyright 2021, Ivyspring International Publisher. (b) Schematic illustration of the antioxidation activity of CeLutNCs. Copied with permission [176]. Copyright 2024, American Chemical Society.

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