Skip to main content
Download PDF

An antioxidant nanozyme for targeted cardiac fibrosis therapy post myocardial infarction

Journal of Nanobiotechnology volume 22, Article number: 760 (2024) Cite this article

A Correction to this article was published on 17 March 2025

This article has been updated

Abstract

The excessive release of reactive oxygen species (ROS) after myocardial infarction (MI) disrupts the natural healing process, leading to cardiac fibrosis and compromising patient prognosis. However, the clinical application of many antioxidant drugs for MI treatment is hindered by their poor antioxidant efficacy and inability to specifically target the heart. Here we developed a tannic acid-modified MnO2 nanozyme (named MnO2@TA), which can achieve cardiac targeting to inhibit post-MI fibrosis and enhance cardiac function. Specifically, the MnO2@TA nanozyme, endowed with superoxide dismutase (SOD) and catalase (CAT) activities, effectively scavenges ROS, suppressing fibroblast activation and mitigating cardiac fibrosis without affecting cardiac repair. Notably, the incorporation of TA improves the nanozyme’s affinity for the elastin and collagen-rich extracellular matrix in cardiac tissues, significantly increasing its retention and uptake within the heart and thereby enhancing its anti-fibrotic efficacy. In a murine myocardial infarction model, MnO2@TA demonstrates remarkable cardiac protection and safety, significantly improving cardiac function while attenuating cardiac fibrosis. This study presents a valuable reference for clinical research aimed at inhibiting cardiac fibrosis and advancing myocardial infarction treatments.

Graphical Abstract

Introduction

Myocardial infarction (MI) remains a leading cause of mortality worldwide, and its consequences require critical attention [1,2,3]. Cardiac fibrosis, characterized by an excessive accumulation of extracellular matrix (ECM) proteins within the cardiac interstitium, is a common pathological remodeling process after MI [4, 5]. While controlled fibroblast proliferation and ECM deposition are critical for maintaining the structural integrity of the infarcted ventricle, uncontrolled fibroblast activation leads to adverse remodeling in MI patients [6]. This aberrant fibroblast activity results in the formation of cardiac fibrotic scars, which subsequently leads to cardiac systolic and diastolic dysfunction, ultimately culminating in heart failure [7, 8]. Transforming growth factor β (TGFβ) is one of the major pro-fibrotic factors, and its pro-fibrotic role in cardiovascular disease has been extensively studied and confirmed [9, 10]. TGFβ induces fibroblast activation by releasing and binding to surface receptors through paracrine and autocrine pathways, thereby initiating downstream signaling and triggering pro-fibrosis signaling cascades [11, 12]. In recent years, drugs targeting TGFβ, such as TGFβ inhibitors, have shown promise in mitigating cardiac fibrosis and have emerged as a potential strategy for managing post-MI cardiac injury [13, 14]. However, these inhibitors face limitations in anti-fibrosis therapy because TGFβ has multiple physiological roles in various normal cells, and direct intervention of TGFβ may produce systemic side effects detrimental to post-MI cardiac repair [13, 15]. Additionally, currently available drugs targeting the neurohumoral pathway, such as renin–angiotensin–aldosterone system (RAAS) inhibitors and β-blockers, offer only partial relief from fibrosis development when regulating the systemic state, making them less effective. Therefore, there is an urgent need for the development of more precisely targeted anti-cardiac fibrosis medications for MI treatment [8, 16, 17].

In recent years, it has been found that reactive oxygen species (ROS) play a key role in the development of cardiac fibrosis [18]. ROS, arising from oxidative stress, including superoxide ions (O2−.), hydrogen peroxide (H2O2), and hydroxyl radicals (–OH) [19]. After myocardial infarction, the heightened release of ROS triggers the activation of tyrosine and serine-threonine kinases, which subsequently activate various signaling pathways such as ERK1/ERK2, Pyk-2/Src/PDK-1, Akt/PKB, and p70S6K to induce a fibrosis phenotype and promote fibroblast activation [19]. In addition, ROS production also exacerbates fibrosis by stimulating TGF-β production, setting off a pro-fibrosis signaling cascade [4, 20]. The fibrosis process mediated by ROS induces structural changes in cardiac tissue, involving excessive fibroblast activation, proliferation, and collagen deposition [21]. Ultimately, these changes cause myocardial hypertrophy, stiffness and impaired ventricular function, culminating in serious conditions such as heart failure [22]. Therefore, the regulation of ROS levels is critical for mitigating cardiac fibrosis [23]. Currently, researchers are dedicated to developing therapeutic strategies targeting ROS, including the use of antioxidants and gene regulation to modulate ROS levels, with the goal of decelerating or reversing the progression of cardiac fibrosis, ultimately protecting cardiac function. Nevertheless, challenges persist, including non-specificity, complexities in dosage control, safety concerns, and technical and cost intricacies [24, 25].

Nanozymes, characterized by their cost-effectiveness, heightened enzyme activity, and multifunctional properties mimicking natural enzymatic functions like superoxide dismutase (SOD) and catalase (CAT), have been proven effective in scavenging reactive oxygen species in a variety of studies [26,27,28,29]. Various functional nanozymes, including manganese, iron, gold, platinum, and cerium, have showcased innovation in addressing ROS-related ailments, holding promising potential for treatment of ROS-related diseases [30,31,32,33,34,35,36]. However, unlike other ROS-related diseases, the special high blood flow in the heart leads to insufficient drug retention at the infarcted myocardium, resulting in limited success in combating cardiac fibrosis using antioxidant drugs including nanozymes, which may also have adverse systemic effects [37, 38]. Therefore, overcoming the high rate of blood flow and increasing the accumulation of nanozymes at the cardiac lesion site is crucial for harnessing their antioxidant capacity in MI treatment. While direct drug delivery to specific heart sites through surgical interventions like sternotomy or open heart surgery is possible, it involves chest wall and bone trauma [39]. There is a growing interest in circulatory system-targeted drug delivery for MI treatment, yet target-specific delivery strategies often face challenges due to inadequate target localization [40, 41]. Encouragingly, recent studies highlight the substantial affinity of tannic acid (TA) for extracellular matrices abundant in the heart, such as elastin and collagen [42]. Modification with TA can significantly enhance drug accumulation at the cardiac site, presenting novel prospects for constructing cardiac-targeted drug delivery systems [43].

In this study, we successfully synthesized MnO2 nanozymes with controllable particle size through albumin-mediated biomineralization. Further surface modification using tannic acid resulted in the development of a novel cardiac-targeted nanozyme, termed MnO2@TA, designed for myocardial infarction therapy. Captitalizing on tannic acid’s affinity for the abundant collagen and elastin in the heart, MnO2@TA efficiently accumulates within cardiac tissues, enhancing the nanozyme’s drug retention by threefold and significantly enhancing fibroblast-mediated drug uptake. In addition, MnO2@TA harnessed its dual enzyme (SOD and CAT)-like properties harnessed to scavenge reactive oxygen species at the infarction site, thereby mitigating the damage to the heart. Importantly, by scavenging reactive oxygen species, MnO2@TA significantly attenuated the activation, proliferation and migration of fibroblasts, consequently inhibiting the occurrence of cardiac fibrosis without compromising cardiac repair. In the MI mouse model, MnO2@TA showed significant cardioprotective effects and safty, improved cardiac function, and attenuated post-infarction cardiac fibrosis damage. This study serves as a valuable clinical research reference for inhibiting cardiac fibrosis and treating myocardial infarction (Scheme 1).

Scheme 1
scheme 1

Schematic illustration of A preparation of tannin acid-modified nanozyme (named as MnO2@TA) and B application for the treatment of myocardial infarction by cardiac-targeted anti-oxidation and anti-fibrosis

Full size image

Results

Preparation and characterization of the MnO2@TA

In this study, we conducted a two-step synthesis of the tannic acid-modified antioxidant-nanozyme (MnO2@TA). Initially, MnO2 nanozyme was synthesized through a biomineralization method. Under alkaline conditions, bovine serum albumin (BSA) was used to effectively sequester Mn2+ ions, leading to the formation of protein-coated MnO2 nanozyme [44]. Subsequently, the TA-modified MnO2 (MnO2@TA) was achieved by introducing tannic acid to the solution with vigorous stirring (Fig. 1A). The solution’s color transitioned from brownish yellow to brown, indicating successful tannic acid modification. (Supplementary Fig. 1B). To determine the optimal TA-capped concentration, we assessed turbidity changes by analysis of absorbance at 600 nm after modification with varying tannic acid concentrations according previous work [42]. With the increase in TA dosage, the absorbance of the solution at 600 nm noticeably rises, reaching a plateau between 500 µM and 2000 µM (Fig. 1B), indicating saturation of TA modification on MnO2 nanozyme under these conditions. Additionally, at 500 µM, the nanoparticles still maintain a uniformly dispersed state, demonstrating good stability (Supplementary Fig. 1A). However, if the TA concentration continues to increase beyond 3000 μm, there is another significant increase in absorbance, largely due to MnO2 nanozyme aggregation (Supplementary Fig. 1A), which is unfavorable for MnO2 modification. Consequently, we selected a tannic acid modification concentration of 500 µM to modify the MnO2 for subsequent experiments.

Fig. 1
figure 1

Preparation, characterization and enzyme-mimic activity of MnO2@TA. A Flow chart for the synthesis of MnO2@TA. B Turbidimetric assay for determining the optimal concentration of tannic acid to modify on the surface of the MnO2. C TEM image of MnO2@TA. Scale bar, 50 nm. D UV–vis spectra of BSA, TA, MnCl2, MnO2 and MnO2@TA. E Hydrodynamic diameters of MnO2@TA. F ABTS radical scavenging ability of MnO2@TA at various concentrations. G Concentration-dependent catalysis of MnO2@TA towards MB based on its UV–vis absorption. H Detection of the oxygen concentration change in different solutions. I Superoxide dismutase (SOD)enzyme activity assay of MnO2@TA. J Catalase (CAT) enzyme activity assay of MnO2@TA. K Schematic illustration showing the conversion of O2−. and H2O2 into non-toxic H2O and O2 by MnO2@TA, mimicking the cascade reaction of various enzymes including SOD and CAT enzyme activities

Full size image

The resulting MnO2@TA nanozyme displayed a uniform morphological distribution with small size, as confirmed by transmission electron microscopy (TEM) analysis (Fig. 1C). UV–visible absorption spectra exhibited characteristic absorption peaks at 280 and 335 nm, corresponding to BSA and MnO2, respectively, confirming the successful synthesis of MnO2 (Fig. 1D) [45]. Dynamic light scattering (DLS) revealed that the hydrodynamic size of MnO2@TA gradually increased following addition of different concentrations of tannic acid (Supplementary Fig. 2A), and the particle size of MnO2@TA with 500 µM tannic acid modification was about 40 nm (Fig. 1E). This further corroborated the effective tannic acid modification. Additionally, the zeta potential demonstrated an increase in the negative potential of the nanoparticles after tannic acid modification (Supplementary Fig. 2B).

Antioxidant activity of MnO2@TA

Reactive oxygen species play a significant role in the progression of cardiac fibrosis, making the scavenging of ROS an effective strategy for anti-fibrosis therapy [46, 47]. Initially, we examined the catalytic activity of MnO2@TA with various substrates. Gradually increasing the MnO2@TA concentration led to the progressive scavenging of ABTS radicals, with 90% of ABTS being scavenged when 100 µg/mL of MnO2@TA was introduced (Fig. 1F). Additionally, we utilized methylene blue (MB), which undergoes oxidation and discoloration in the presence of hydroxyl radicals, to assess MnO2@TA’s ·OH scavenging ability through changes in MB absorbance. As depicted in Fig. 1G, escalating MnO2@TA concentrations correlated with increased MB absorbance, indicating enhanced ·OH scavenging. Subsequently, we reacted MnO2@TA with hydrogen peroxide, revealing a substantial increase in oxygen generation and hydrogen peroxide substrate consumption (Fig. 1H). Collectively, these findings confirm MnO2@TA’s effective scavenging of various free radicals. We also assessed the impact of MnO2@TA on the activities of various enzymes. SOD catalyzes O2−. to produce H2O2, while CAT catalyzes the decomposition of H2O2 into non-toxic H2O and O2, which is a key step in the ROS clearance cascade process. Using enzyme activity detection kits to detect the enzymes activity of MnO2@TA with different concentrations. The results indicated that the activities of SOD and CAT increased progressively with rising MnO2@TA concentrations (Fig. 1I, J), suggesting that MnO2@TA exerts its antioxidant effects through the activities of both SOD and CAT enzymes. To better assess the enzyme activities of MnO2@TA, we compared its SOD and CAT activities with those of Trolox, a conventional antioxidant, and CeO2, a classical nanozyme (Supplementary Fig. 3). The results indicated that Trolox exhibited no significant SOD or CAT activity, as it functions solely as an antioxidant and lacks enzyme-like activity. In contrast, MnO2@TA displayed stronger SOD and CAT activities than CeO2, confirming its efficient enzyme-mimicking capabilities. Furthermore, the results of electron paramagnetic resonance (EPR) experiments confirmed that MnO2@TA also exhibits superoxide dismutase (SOD) and catalase (CAT) enzyme activities, enabling it to scavenge ·O2− and H2O2 (Supplementary Fig. 4). In summary, based on the analysis of SOD-like and CAT-like activities, the optimized MnO2@TA demonstrated antioxidant activity by converting O2−. into nontoxic molecules through catalyzed cascade reactions involving SOD and CAT (Fig. 1K).

Cardiac targeting ability of MnO2@TA

The extracellular matrix represents non-cellular component of the cardiac microenvironment, primarily consisting of collagen and elastin, filling the intercellular matrix [21, 48]. Previous studies have found TA’s notable affinity for the extracellular matrix, suggesting its potential to enhance the retention of TA-modified MnO2 nanozymes in the heart (Fig. 2A). To verify MnO2@TA’s affinity, we employed MnO2 nanozyme as a control to compare their interaction with elastin and type 1 collagen. The results showed an increase in turbidity of MnO2@TA following the addition of elastin and collagen solutions. In contrast, MnO2 showed no discernible change in turbidity upon adding elastin and collagen (Fig. 2B). These results suggest that TA modification enhances the nanozymes’ affinity for the extracellular matrix. Subsequently, Mouse Cardiac Fibroblasts (MCFs) were seeded onto culture dishes pre-coated with collagen, and then Cy5-labeled MnO2@TA was subsequently added to investigate the enhanced targeting of the MnO2@TA toward cardiac fibroblasts. Confocal imaging revealed a gradual increase in the red fluorescence intensity of MCFs over time, signifying an incremental endocytosis of nanozymes by MCFs (Fig. 2C). Notably, MnO2@TA exhibited a significantly higher endocytosis effect compared to MnO2 at various time intervals (Fig. 2D). The high affinity of TA for the ECM leads to increased accumulation of MnO2@TA near the MCFs and increased the spatiotemporal opportunities of MCFs engulfing MnO2@TA.This enhanced targeting was further affirmed by flow cytometry analysis, demonstrating that MnO2@TA exhibited superior cellular uptake after co-incubation with MCFs for 2 h (Fig. 2E, F). It is worth noting that tannic acid contains abundant hydrophobic and hydrogen bonds, which may bind to plasma proteins, such as albumin, thereby influencing its targeting capability. To assess the impact of plasma proteins on the nanozyme, we conducted a 24-hour study on the stability of MnO2@TA in a solution containing fetal bovine serum (FBS). Our findings indicate that the presence of plasma proteins did not alter the size or zeta potential of MnO2@TA (Supplementary Fig. 5). Furthermore, we evaluated whether the addition of serum to the fibroblast medium affected the uptake of the nanozyme by the fibroblasts. The results showed no significant difference in uptake (Supplementary Fig. 6).

Fig. 2
figure 2

TA modification facilitates cardiac targeting of MnO2@TA. A Schematic illustration showing the enhanced binding of MnO2@TA to the extracellular matrix, thereby increasing its cardiac residency. B Turbidity changes of MnO2 and MnO2@TA when mixed with elastin and collagen type 1 solutions. C Cellular uptake of Cy5-labeled MnO2 and MnO2@TA on MCFs cells in a 24-well plate at different times points. D Quantitative statistics of Cy5 fluorescence intensity in panel C. E Flow cytometry of fluorescence intensity in MCFs when incubated with cy5-labeled MnO2 and MnO2@TA for 2 h. F Quantitative statistics of Cy5 fluorescence intensity in panel E. G The fluorescence intensity of IR1061-labeled MnO2@TA in various organs at different time intervals after tail vein injection (n = 3 per group). H The fluorescence intensity of IR1061-labeled MnO2 and MnO2@TA in each organ after 8 h of tail vein injection in Sham and MI mice (n = 3 per group). Data are presented as mean ± s.d. *P < 0.05, **P < 0.01, and ***P < 0.001

Full size image

Furthermore, we investigated the targeting and retention of IR1061-labeled MnO2@TA and MnO2 in the heart using mouse intravenous injection models. Mice were injected with IR1061-labeled MnO2@TA through the tail vein, and an infrared two-region imaging system was used to photograph the heart, liver, spleen, lungs, and kidneys at 1, 2, 4, 8, and 16 h. The fluorescence in the heart gradually increased from the 2nd hour and reached a maximum at the 8th hour. The kidney exhibited heightened fluorescence intensity at 16 h, indicating gradual metabolism of MnO2@TA (Fig. 2G). In addition, the pharmacokinetics of MnO2@TA was investigated after intravenous injection of Cy5-labeled MnO2@TA. The results showed that the distribution and elimination phases of MnO2@TA were 0.6 ± 0.2 h and 2.5 ± 1.1 h, respectively, which are similar to the metabolic times reported for other nanozyme drugs (Supplementary Fig. 7) [25, 49]. Furthermore, after intravenous administration, we collected mouse urine and feces at different time points and measured the Mn²⁺ content to assess its metabolic process. The results showed that Mn2⁺ was excreted through both urine and feces, with a higher proportion being excreted through urine (Supplementary Fig. 8). Moreover, the nanoparticles were gradually metabolized within 3 days. This is likely because Mn2⁺, as a metal ion, is more readily eliminated via the kidneys.

We subsequently compared the cardiac targeting ability of MnO2@TA in normal and MI mice. The results revealed that MnO2 exhibited weak fluorescence in normal mice, with slightly elevated fluorescence intensity in MI mice, potentially due to the enhanced permeability and retention (EPR) effect in damaged tissues post-MI. In contrast, after MnO2@TA injection, the fluorescence intensity in the heart substantially increased in both normal and MI mice, underscoring MnO2@TA’s cardiac-targeting effect (Fig. 2H and Supplementary Fig. 9). Collectively, these findings affirm MnO2@TA’s preferential affinity for cardiac-enriched elastin and collagen, likely enhancing its accumulation at cardiac sites.

MnO2@TA attenuates oxidative stress and fibrosis in MCFs

To investigate the therapeutic effect of MnO2@TA on fibrosis, we used TGFβ to stimulate mouse fibroblast MCFs to induce a fibrosis phenotype [50, 51]. Cell viability was assessed via a CCK8 assay following a 24-h co-incubation of various TGFβ concentrations with MCFs. The data revealed that 10 ng/mL of TGFβ was the optimal concentration for MCFs stimulation (Supplementary Fig. 10), and this concentration was consistently employed to induce MCFs differentiation in all subsequent experiments. Initially, to determine the safe concentration of MnO2@TA, we performed CCK8 assays on both MCFs and H9C2 cells. The results demonstrated minimal cytotoxicity even at a high concentration of 50 µg/mL of MnO2@TA (Supplementary Fig. 11A, B). Consequently, we selected a concentration of 25 µg/mL of MnO2@TA for subsequent cell treatments.

Previous research has implicated oxidative stress as a pivotal factor in fibrosis development. TGFβ stimulation of MCFs has been shown to elicit high NOX4 expression and ROS production [19, 52]. ROS-induced conformational changes in the precursor of TGFβ, LAP, lead to the release of TGFβ [53]. As such, we initiated our investigation by examining the impact of TGFβ stimulation on intracellular ROS levels through DCFH-DA staining. The results indicated a marked increase in intracellular ROS levels in TGFβ-stimulated MCFs, denoted by strong green fluorescent signals within the cells. In contrast, MCFs treated with MnO2@TA displayed a significant reduction in the fluorescent signal, signifying a substantial attenuation of intracellular ROS levels (Fig. 3A). Furthermore, we quantified ROS levels through flow cytometry, which consistently demonstrated a significant reduction in intracellular ROS levels following MnO2@TA treatment (Fig. 3B, C). Given that cardiomyocytes in the heart are also affected by ROS, we evaluated ROS levels in cardiomyocytes. Using fluorescence microscopy and flow cytometry analysis, our findings suggest that MnO2@TA is equally effective in attenuating ROS levels in cardiomyocytes (Supplementary Fig. 12A­–C).

Fig. 3
figure 3

In vitro anti-oxidant ability of MnO2@TA to mitigate MCFs activation. A Visualization of the ROS level of MCFs cells after different treatments using DCFH-DA. Scale bar, 100 μm. B Flow cytometry analysis of DCFH-DA fluorescence intensity in MCFs after different treatments. C Quantitative statistics of fluorescence intensity in panel B. D Protein expression levels of fibrosis-related proteins in treated MCFs. E Quantitative statistics of protein expression levels of fibrosis-related protein. F 5-ethynyl-2′-deoxyuridine (EDU) assay to evaluate the proliferation ability of MCFs. G Quantitative statistics of fluorescence intensity of EDU assay. H Cell scratch assay to evaluate the migration ability of MCFs. I Quantitative statistics of the degree of migration of MCFs. J Schematic illustration showing that MnO2@TA attenuates the fibrosis-related phenotype of MCFs through antioxidation. Data are presented as mean ± s.d. *P < 0.05, **P < 0.01, and ***P < 0.001

Full size image

To evaluate MCFs differentiation, we examined the expression of fibrosis-related proteins via western blot analysis, which serve as indicators of ECM secretion and MCFs differentiation, respectively [54, 55]. Our data revealed that TGFβ-treated MCFs exhibited a substantial increase in the expression of fibrosis-related proteins. In contrast, MCFs pre-treated with MnO2@TA exhibited a significant mitigation of the pro-differentiation effect induced by TGFβ (Fig. 3D). The expression of proteins α-SMA and Periostin, representing fibroblast activation-related proteins, and Collagen1 and Fibronectin, representing extracellular matrix secretion-related proteins, were significantly downregulated (Fig. 3E). Increased proliferation and migration capabilities are key features of fibroblasts following differentiation. 5-ethynyl-2′-deoxyuridine (EDU) staining allowed for the identification of proliferating cells in the S phase of the cell cycle. Our data demonstrated that MnO2@TA-treated cells significantly reduced the proliferative capacity of activated MCFs (Fig. 3F, G). Similarly, a comparison of migration assays conducted after 24 h indicated that MCFs treated with MnO2@TA exhibited reduced migratory ability in contrast to those stimulated with TGFβ alone (Fig. 3H, I). Collectively, our proliferation and migration assays further underscored the inhibitory effects of MnO2@TA on the pro-fibrosis actions of TGFβ (Fig. 3J).

MnO2@TA improves cardiac function and alleviates cardiac fibrosis

Following the validation of the anti-fibrosis properties of MnO2@TA in vitro, we proceeded to assess its in vivo efficacy and determine whether targeted delivery could enhance its therapeutic potential. Post-MI mice were administered 1 mg/kg of MnO2@TA via the tail vein every 3 days for a duration of 4 weeks. On day 28, echocardiography was conducted to evaluate cardiac function (Fig. 4A). Intravenous administration is a prevalent approach in the treatment of heart diseases. Furthermore, tail vein injection contributes to exploring the cardiac targeting of MnO2@TA in this study.

Fig. 4
figure 4

Cardiac-targeted therapy with MnO2@TA improves cardiac function after myocardial infarction. A Experimental schedule detailing the treatment regimen for MI mice with MnO2@TA. B Survival curves for each group of mice (n = 12 per group). C Echocardiographic images of mice hearts after different treatments. D Quantification of left ventricular ejection fractions (LVEF), fractional shortening (FS), left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) in mice with MI after various treatments (n = 6). E Wheat germ agglutinin (WGA) staining showing myocardial hypertrophy after different treatments. Scale bar, 40 µM. F Quantitative statistics of WGA staining (n = 6 per group). Data are presented as mean ± s.d. *P < 0.05, **P < 0.01, and ***P < 0.001

Full size image

Post-myocardial infarction, MI-afflicted mice experienced severe heart failure and adverse cardiac remodeling due to cardiac fibrosis, negatively impacting ventricular function. Survival curves revealed that mice treated with saline following MI had the lowest survival rate, while treatment with MnO2@TA exhibited the most significant increase in survival (Fig. 4B). Echocardiographic images displayed enhanced ventricular wall systolic function after 28 days of treatment with both MnO2 and MnO2@TA (Fig. 4C). Quantitative analysis indicated that MI mice injected with saline experienced a marked decrease in left ventricular ejection fractions (LVEF) and fractional shortening (FS), along with a significant increase in left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). Administration of both MnO2 and MnO2@TA mitigated the decline in cardiac function postinfarction. Notably, MnO2@TA outperformed MnO2 in enhancing cardiac function, achieving statistically significant improvements in LVEF, FS, and LVEDV, while also exhibiting superior therapeutic effects, albeit without statistically significant changes in LVESV (Fig. 4D). Wheat germ agglutinin (WGA) staining revealed varying degrees of myocardial hypertrophy in infarcted mice, with MnO2@TA treatment minimizing adverse remodeling to the greatest extent (Fig. 4E).

Furthermore, we evaluated post-infarction fibrosis within the mouse myocardium through histological examination. Masson staining indicated extensive fibrosis in mice 28 days post-MI, with both MnO2 and MnO2@TA offering varying degrees of improvement, albeit the smallest fibrosis area observed in MnO2@TA-treated mice (Fig. 5A and Supplementary Figs. 13A and 23). Similarly, HE staining showed the smallest area of cardiac damage in MnO2@TA-treated mice. Protein blot analysis of cardiac tissues demonstrated significant reductions in fibrosis-related phenotypes in MnO2@TA-treated mice (Fig. 5B). Compared to MnO2, MnO2@TA significantly attenuated the expression of fibrosis-related proteins (Supplementary Fig. 13B). In addition, we investigated tissue levels of oxidative stress. Oxidative stress within tissues leads to lipid oxidation, with malondialdehyde (MDA), a lipid oxidation byproduct, reflecting the level of oxidative stress [56]. We assayed MDA levels in the myocardium to validate the capacity of MnO2@TA in reducing tissue reactive oxygen species levels (Fig. 5C). Subsequently, we stained cardiac tissue for reactive oxygen species, with dihydroethidium (DHE) red fluorescence serving as an indicator of tissue reactive oxygen species levels [57]. In accordance with previous findings, MnO2@TA exhibited significant reductions in tissue reactive oxygen species levels (Fig. 5D and Supplementary Fig. 13C). These results confirm the considerable capacity of MnO2@TA to attenuate post-infarction myocardial fibrosis by targeting the heart to mitigate ROS.

Fig. 5
figure 5

Cardiac-targeted therapy with MnO2@TA attenuates cardiac fibrosis. A Representative Masson’s trichrome and HE images depicting the extent of cardiac fibrosis in mice hearts after different treatments (n = 6 per group). Scale bars, 1 mm and 50 µM. B Western blot analysis illustrating the levels of cardiac fibrosis-related proteins in mice hearts after different treatments (n = 6 per group). C Measurement of tissue malondialdehyde (MDA) levels in the myocardium providing insight into oxidative stress (n = 6 per group). D Dihydroethidium (DHE) staining showing the level of ROS in the myocardium (n = 6 per group). Scale bar, 50 µM. Data are presented as mean ± s.d. *P < 0.05, **P < 0.01, and ***P < 0.001

Full size image

Finally, we evaluated the stability and biosafety of MnO2@TA under in vivo physiological conditions. In solutions containing mouse serum and healthy human serum, MnO2@TA maintained relatively good colloid stability with no obvious change in size and zeta potential within 24 h (Supplementary Figs. 14, 15), confirming the stability of the MnO2@TA under in vivo physiological conditions. And the addition of different concentrations of MnO2@TA did not lead to the occurrence of hemolytic reactions (Supplementary Fig. 16). To assess the safety of MnO2@TA after intravenous injection, we compared the multiorgan functions of normal mice and mice injected intravenously with MnO2@TA after 28 days. Blood biochemistry showed no significant differences in liver and kidney (Supplementary Fig. 17A–C). Echocardiography also showed consistent cardiac function in both (Supplementary Fig. 17D). Moreover, HE staining confirmed the absence of toxic accumulation or damage to major tissues (Supplementary Fig. 18). To further assess hepatotoxicity, we performed TUNEL staining to detect hepatocyte apoptosis. The results indicated that MnO2@TA injection did not induce hepatocyte apoptosis (Supplementary Fig. 19). Additionally, to determine whether MnO2@TA could trigger an abnormal immune response, we measured the levels of IL-6 and TNF-α in the serum of the mice. Our findings showed no significant immune response following nanozyme injection, suggesting the in vivo safety of MnO2@TA (Supplementary Fig. 20).

Conclusion

Cardiac fibrosis following myocardial infarction presents a significant clinical challenge, and currently, no specific treatment is available. In recent years, oxidative stress has been identified as playing a key role in fibrosis progression. By scavenging reactive oxygen species (ROS), activation and proliferation of fibroblasts can be reduced, and ventricular remodeling in the damaged heart can be alleviated. However, due to the high blood flow in the heart, drugs often fail to accumulate sufficiently, necessitating higher doses, which may increase the potential toxicity of the drugs.

In this work, we successfully employed albumin for the biomineralization of MnO2 nanozymes and further surface-modified them with tannic acid, yielding a new heart-targeting nanozyme, MnO2@TA. Capitalizing on tannic acid, MnO2@TA effectively accumulates in cardiac tissue, addressing challenges associated with inadequate drug targeting due to the high blood flow areas of the heart. Moreover, the enhanced cardiac targeting significantly improves MnO2@TA’s efficacy in ROS clearance at the infarct site, thereby reducing cardiac damage. It is worth noting that this ROS clearance also inhibits the fibroblast activation, and suppresses cardiac fibrosis without affecting cardiac repair. In a mouse model of myocardial infarction, MnO2@TA exhibits remarkable cardioprotective effects, resulting in improved cardiac function and a reduction in post-infarction cardiac fibrosis-related injuries. Additionally, the nanozyme shows high stability under physiological conditions and does not induce hemolysis or immune adverse reactions, supporting its safety and efficacy as a new drug with promising clinical translation prospects. This study offers valuable clinical insights for those seeking to inhibit cardiac fibrosis and enhance the treatment of myocardial infarction.

Data availability

No datasets were generated or analysed during the current study.

Change history

References

  1. van den Borne SW, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J. Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol. 2010;7:30–7.

    Article  PubMed  Google Scholar 

  2. Bergmark BA, Mathenge N, Merlini PA, Lawrence-Wright MB, Giugliano RP. Acute coronary syndromes. Lancet. 2022;399:1347–58.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bhatt DL, Lopes RD, Harrington RA. Diagnosis and treatment of acute coronary syndromes: a review. JAMA. 2022;327:662–75.

    Article  PubMed  Google Scholar 

  4. Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021;117:1450–88.

    Article  CAS  PubMed  Google Scholar 

  5. Hinderer S, Schenke-Layland K. Cardiac fibrosis—a short review of causes and therapeutic strategies. Adv Drug Deliv Rev. 2019;146:77–82.

    Article  CAS  PubMed  Google Scholar 

  6. Tallquist MD. Cardiac fibroblast diversity. Annu Rev Physiol. 2020;82:63–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tallquist MD, Molkentin JD. Redefining the identity of cardiac fibroblasts. Nat Rev Cardiol. 2017;14:484–91.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Frangogiannis NG. Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities. Mol Aspects Med. 2019;65:70–99.

    Article  CAS  PubMed  Google Scholar 

  9. Frangogiannis N. Transforming growth factor-β in tissue fibrosis. J Exp Med. 2020;217:e20190103.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gao P, Li L, Ji L, Wei Y, Li H, Shang G, Zhao Z, Chen Q, Jiang T, Zhang N. Nrf2 ameliorates diabetic nephropathy progression by transcriptional repression of TGFβ1 through interactions with c-Jun and SP1. Biochim Biophys Acta. 2014;1839:1110–20.

    Article  CAS  PubMed  Google Scholar 

  11. Hanna A, Frangogiannis NG. The role of the TGF-β superfamily in myocardial infarction. Front Cardiovasc Med. 2019;6:140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007;74:184–95.

    Article  CAS  PubMed  Google Scholar 

  13. Akhurst RJ, Hata A. Targeting the TGFβ signalling pathway in disease. Nat Rev Drug Discov. 2012;11:790–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gao P, Li L, Yang L, Gui D, Zhang J, Han J, Wang J, Wang N, Lu J, Chen S, et al. Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFβ1. Sci Transl Med. 2019;11:eaaw2050.

    Article  CAS  PubMed  Google Scholar 

  15. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71:549–74.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Q, Wang L, Wang S, Cheng H, Xu L, Pei G, Wang Y, Fu C, Jiang Y, He C, Wei Q. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther. 2022;7:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zheng H, Liang X, Han Q, Shao Z, Zhang Y, Shi L, Hong Y, Li W, Mai C, Mo Q, et al. Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence. J Nanobiotechnol. 2021;19:332.

    Article  CAS  Google Scholar 

  18. Faria A, Persaud SJ. Cardiac oxidative stress in diabetes: mechanisms and therapeutic potential. Pharmacol Ther. 2017;172:50–62.

    Article  CAS  PubMed  Google Scholar 

  19. Barnes JL, Gorin Y. Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 2011;79:944–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Purnomo Y, Piccart Y, Coenen T, Prihadi JS, Lijnen PJ. Oxidative stress and transforming growth factor-β1-induced cardiac fibrosis. Cardiovasc Hematol Disord Drug Targets. 2013;13:165–72.

    Article  CAS  PubMed  Google Scholar 

  21. Li L, Zhao Q, Kong W. Extracellular matrix remodeling and cardiac fibrosis. Matrix Biol. 2018;68–69:490–506.

    Article  PubMed  Google Scholar 

  22. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol. 2018;15:387–407.

    Article  CAS  PubMed  Google Scholar 

  23. Grosche J, Meißner J, Eble JA. More than a syllable in fib-ROS-is: the role of ROS on the fibrotic extracellular matrix and on cellular contacts. Mol Aspects Med. 2018;63:30–46.

    Article  CAS  PubMed  Google Scholar 

  24. Wang H, Wan K, Shi X. Recent advances in nanozyme research. Adv Mater. 2019;31:e1805368.

    Article  PubMed  Google Scholar 

  25. Liu X, Li F, Dong Z, Gu C, Mao D, Chen J, Luo L, Huang Y, Xiao J, Li Z, et al. Metal-polyDNA nanoparticles reconstruct osteoporotic microenvironment for enhanced osteoporosis treatment. Sci Adv. 2023;9:eadf3329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yuan R, Li Y, Han S, Chen X, Chen J, He J, Gao H, Yang Y, Yang S, Yang Y. Fe-curcumin nanozyme-mediated reactive oxygen species scavenging and anti-inflammation for acute lung injury. ACS Cent Sci. 2022;8:10–21.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Y, Khalique A, Du X, Gao Z, Wu J, Zhang X, Zhang R, Sun Z, Liu Q, Xu Z, et al. Biomimetic design of mitochondria-targeted hybrid nanozymes as superoxide scavengers. Adv Mater. 2021;33:e2006570.

    Article  PubMed  Google Scholar 

  28. Guo Z, Hong J, Song N, Liang M. Single-atom nanozymes: from precisely engineering to extensive applications. Acc Mater Res. 2024;5:347–57.

    Article  CAS  Google Scholar 

  29. Yu Y, Zhang Y, Wang Y, Chen W, Guo Z, Song N, Liang M. Multiscale structural design of MnO2@GO superoxide dismutase nanozyme for protection against antioxidant damage. Nano Res. 2023;16:10763–9.

    Article  CAS  Google Scholar 

  30. Liu H, Li Y, Sun S, Xin Q, Liu S, Mu X, Yuan X, Chen K, Wang H, Varga K, et al. Catalytically potent and selective clusterzymes for modulation of neuroinflammation through single-atom substitutions. Nat Commun. 2021;12:114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu XL, Dong X, Yang SC, Lai X, Liu HJ, Gao Y, Feng HY, Zhu MH, Yuan Y, Lu Q, et al. Biomimetic liposomal nanoplatinum for targeted cancer chemophototherapy. Adv Sci. 2021;8:2003679.

    Article  CAS  Google Scholar 

  32. Wang L, Qiu S, Li X, Zhang Y, Huo M, Shi J. Myocardial-targeting tannic cerium nanocatalyst attenuates ischemia/reperfusion injury. Angew Chem Int Ed Engl. 2023;135:e202305576.

    Article  Google Scholar 

  33. Cheng G, Liu X, Liu Y, Liu Y, Ma R, Luo J, Zhou X, Wu Z, Liu Z, Chen T, Yang Y. Ultrasmall coordination polymers for alleviating ROS-mediated inflammatory and realizing neuroprotection against Parkinson’s disease. Research. 2022;2022:9781323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ge J, Yang L, Li Z, Wan Y, Mao D, Deng R, Zhou Q, Yang Y, Tan W. A colorimetric smartphone-based platform for pesticides detection using Fe-N/C single-atom nanozyme as oxidase mimetics. J Hazard Mater. 2022;436:129199.

    Article  CAS  PubMed  Google Scholar 

  35. Chen Y, Jiang B, Hao H, Li H, Qiu C, Liang X, Qu Q, Zhang Z, Gao R, Duan D, et al. Atomic-level regulation of cobalt single-atom nanozymes: engineering high-efficiency catalase mimics. Angew Chem Int Ed Engl. 2023;62:e202301879.

    Article  CAS  PubMed  Google Scholar 

  36. Ji S, Jiang B, Hao H, Chen Y, Dong J, Mao Y, Zhang Z, Gao R, Chen W, Zhang R, et al. Matching the kinetics of natural enzymes with a single-atom iron nanozyme. Nat Catal. 2021;4:407–17.

    Article  CAS  Google Scholar 

  37. Takahama H, Minamino T, Asanuma H, Fujita M, Asai T, Wakeno M, Sasaki H, Kikuchi H, Hashimoto K, Oku N, et al. Prolonged targeting of ischemic/reperfused myocardium by liposomal adenosine augments cardioprotection in rats. J Am Coll Cardiol. 2009;53:709–17.

    Article  CAS  PubMed  Google Scholar 

  38. Liu Q, Zhang A, Wang R, Zhang Q, Cui D. A review on metal- and metal oxide-based nanozymes: properties, mechanisms, and applications. Nanomicro Lett. 2021;13:154.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Huang S, Lei D, Yang Q, Yang Y, Jiang C, Shi H, Qian B, Long Q, Chen W, Chen Y, et al. A perfusable, multifunctional epicardial device improves cardiac function and tissue repair. Nat Med. 2021;27:480–90.

    Article  PubMed  Google Scholar 

  40. Shi HT, Huang ZH, Xu TZ, Sun AJ, Ge JB. New diagnostic and therapeutic strategies for myocardial infarction via nanomaterials. EBioMedicine. 2022;78:103968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang J, Guo Y, Bai Y, Wei Y. Application of biomedical materials in the diagnosis and treatment of myocardial infarction. J Nanobiotechnol. 2023;21:298.

    Article  Google Scholar 

  42. Shin M, Lee HA, Lee M, Shin Y, Song JJ, Kang SW, Nam DH, Jeon EJ, Cho M, Do M, et al. Targeting protein and peptide therapeutics to the heart via tannic acid modification. Nat Biomed Eng. 2018;2:304–17.

    Article  CAS  PubMed  Google Scholar 

  43. Liu X, Chen B, Chen J, Wang X, Dai X, Li Y, Zhou H, Wu LM, Liu Z, Yang Y. A cardiac-targeted nanozyme interrupts the inflammation-free radical cycle in myocardial infarction. Adv Mater. 2023;36:e2308477.

    Article  PubMed  Google Scholar 

  44. Wang F, Wen L, Liu J, Peng W, Meng Z, Chen Q, Wang Y, Ke B, Guo Y, Mi P. Albumin nanocomposites with MnO(2)/Gd(2)O(3) motifs for precise MR imaging of acute myocardial infarction in rabbit models. Biomaterials. 2020;230:119614.

    Article  CAS  PubMed  Google Scholar 

  45. Pardhiya S, Priyadarshini E, Rajamani P. In vitro antioxidant activity of synthesized BSA conjugated manganese dioxide nanoparticles. SN Appl Sci. 2020;2:1597.

    Article  CAS  Google Scholar 

  46. Yao H, He Q, Huang C, Wei S, Gong Y, Li X, Liu W, Xu Z, Wu H, Zheng C, Gao Y. Panaxatriol saponin ameliorates myocardial infarction-induced cardiac fibrosis by targeting Keap1/Nrf2 to regulate oxidative stress and inhibit cardiac-fibroblast activation and proliferation. Free Radic Biol Med. 2022;190:264–75.

    Article  CAS  PubMed  Google Scholar 

  47. Chen RR, Fan XH, Chen G, Zeng GW, Xue YG, Liu XT, Wang CY. Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/ TGFβ1/Smad2/3 signaling axis. Chem Biol Interact. 2019;302:11–21.

    Article  CAS  PubMed  Google Scholar 

  48. Long Y, Niu Y, Liang K, Du Y. Mechanical communication in fibrosis progression. Trends Cell Biol. 2022;32:70–90.

    Article  CAS  PubMed  Google Scholar 

  49. Yang Y, Liu J, Liang C, Feng L, Fu T, Dong Z, Chao Y, Li Y, Lu G, Chen M, Liu Z. Nanoscale metal-organic particles with rapid clearance for magnetic resonance imaging-guided photothermal therapy. ACS Nano. 2016;10:2774–81.

    Article  CAS  PubMed  Google Scholar 

  50. Janbandhu V, Tallapragada V, Patrick R, Li Y, Abeygunawardena D, Humphreys DT, Martin E, Ward AO, Contreras O, Farbehi N, et al. Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell Stem Cell. 2022;29:281–e297212.

    Article  CAS  PubMed  Google Scholar 

  51. Ji X, Meng Y, Wang Q, Tong T, Liu Z, Lin J, Li B, Wei Y, You X, Lei Y, et al. Cysteine-based redox-responsive nanoparticles for fibroblast-targeted drug delivery in the treatment of myocardial infarction. ACS Nano. 2023;17:5421–34.

    Article  CAS  PubMed  Google Scholar 

  52. Cucoranu I, Clempus R, Dikalova A, Phelan PJ, Ariyan S, Dikalov S, Sorescu D. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005;97:900–7.

    Article  CAS  PubMed  Google Scholar 

  53. Siani A, Tirelli N. Myofibroblast differentiation: main features, biomedical relevance, and the role of reactive oxygen species. Antioxid Redox Signal. 2014;21:768–85.

    Article  CAS  PubMed  Google Scholar 

  54. Liao R, Qi Z, Tang R, Wang R, Wang Y. Methyl ferulic acid attenuates human cardiac fibroblasts differentiation and myocardial fibrosis by suppressing pRB-E2F1/CCNE2 and RhoA/ROCK2 pathway. Front Pharmacol. 2021;12:714390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liao R, Xie B, Cui J, Qi Z, Xue S, Wang Y. E2F transcription factor 1 (E2F1) promotes the transforming growth factor TGF-β1 induced human cardiac fibroblasts differentiation through promoting the transcription of CCNE2 gene. Bioengineered. 2021;12:6869–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Qi Z, Liu R, Ju H, Huang M, Li Z, Li W, Wang Y. microRNA-130b-3p attenuates septic cardiomyopathy by regulating the AMPK/mTOR signaling pathways and directly targeting ACSL4 against ferroptosis. Int J Biol Sci. 2023;19:4223–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang Y, Ying X, Wang Y, Zou Z, Yuan A, Xiao Z, Geng N, Qiao Z, Li W, Lu X, Pu J. Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3-NFS1 axis in doxorubicin-induced cardiotoxicity. Cell Signal. 2023;107:110655.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key Research and Development Program of China (No. 2023YFA0915400, 2022YFA1206500), the Fundamental Research Funds for the Central Universities (No. 2020JCPT02), the National Natural Science Foundation of China (No. 22277072, 22107065, 82271608, 82171884, 3240100111), the Natural Science Foundation of Shanghai (No. 24ZR1462700), the Oriental Talents of Pudong Health Bureau of Shanghai (No. 2025PDWSYCQN-08), the Science and Technology Development Fund of Shanghai Pudong New Area (No. PKJ2024-Y40), “Clinic Plus” Outstanding Project (No. 2021ZYB009, 2023ZYB006, 2024ZY005) from Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, and Innovative research team of high-level local universities in Shanghai.

Author information

Author notes

  1. Ziyi Gu and Xueliang Liu contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Medicine (IMM), department of Cardiovascular Surgery, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China

    Ziyi Gu, Xueliang Liu, Zhou Fang, Yiting Jiang, Yuting Huang, Yongyi Wang & Yu Yang

  2. Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410008, China

    Zhen Qi

  3. Department of Radiology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, 200240, China

    Lianming Wu

  4. Punan Branch of Renji Hospital, Shanhai Jiaotong University School of Medicine, Shanghai, 200125, China

    Xueliang Liu

Authors
  1. Ziyi Gu
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Xueliang Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Zhen Qi
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Zhou Fang
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Yiting Jiang
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Yuting Huang
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Yongyi Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Lianming Wu
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Yu Yang
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Conceptualization: Yongyi Wang, Lianming Wu and Yu Yang. Methodology: Ziyi Gu and Xueliang Liu. Validation: Yu Yang, Ziyi Gu and Xueliang Liu. Formal analysis: Yu Yang, Ziyi Gu and Xueliang Liu. Investigation: Zhou Fang, Yiting Jiang, Zhen Qi, Yuting Huang, Ziyi Gu and Xueliang Liu. Data curation: Xueliang Liu. Writing (original draft): Yu Yang, Ziyi Gu and Xueliang Liu. Writing (review and editing): Yu Yang, Ziyi Gu and Xueliang Liu. Visualization: Yu Yang . Supervision: Yongyi Wang, Lianming Wu and Yu Yang. Project administration: Yongyi Wang, Lianming Wu and Yu Yang. Funding acquisition: Yu Yang.

Corresponding authors

Correspondence to Yongyi Wang, Lianming Wu or Yu Yang.

Ethics declarations

Ethics approval and consent to participate

The animal experiments were conducted with the approval of the Animal Care and Use Ethics Committee of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine.

Consent for publication

All the authors have approved the manuscript to publish.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article has been revised: the affiliation details for Ziyi Gu has been updated.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gu, Z., Liu, X., Qi, Z. et al. An antioxidant nanozyme for targeted cardiac fibrosis therapy post myocardial infarction. J Nanobiotechnol 22, 760 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12951-024-03047-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12951-024-03047-6

Keywords

Journal of Nanobiotechnology

ISSN: 1477-3155

Contact us