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Literature Interpretation: Chiral metal nanozyme-enabled SOD2 activation and siRNA delivery cooperatively mitigating chronic heart failure

I. Research Background

Doxorubicin (DOX), a widely used anthracycline chemotherapeutic in clinical practice, has outstanding antitumor efficacy but is a double-edged sword with significant risks. Its cumulative cardiotoxicity can induce persistent myocardial injury and progress to irreversible chronic heart failure, severely restricting the long-term safe application of chemotherapy regimens and threatening the long-term prognosis of cancer survivors.

Existing mechanistic studies indicate that the core driving pathway of DOX-mediated myocardial injury is ferroptosis: after drug intervention, myocardial iron homeostasis is imbalanced, free iron accumulates, and the activity of the key mitochondrial antioxidant protein SOD2 is inhibited. Large amounts of reactive oxygen species accumulate, jointly amplifying lipid peroxidation injury and forming an oxidative damage cascade. Current conventional cardioprotective drugs act on a single pathway, making it difficult to simultaneously achieve synergistic intervention in antioxidation and iron metabolism regulation. Moreover, myocardial-targeted delivery vehicles are lacking, and the clinical intervention effect is limited. Small-animal echocardiography, as a core in vivo imaging modality for dynamically assessing cardiac function and validating heart failure efficacy, plays a key evaluative role in such animal model studies.

To address this dilemma, the team led by Dongdong Sun from Anhui Agricultural University, the team led by Cundong Fan from Shandong First Medical University, and the team led by Kelong Fan from the Institute of Biophysics, Chinese Academy of Sciences, published their work in the top journal Bioactive Materials. They constructed a platelet–macrophage membrane co-modified biomimetic chiral manganese dioxide (L-MnO₂) nanozyme, which possesses both catalase (CAT)-like and superoxide dismutase (SOD)-like activities. It can release Mn²⁺ to activate endogenous SOD2 and simultaneously load siHmox1 to silence a key ferroptosis gene, synergistically blocking iron overload and oxidative stress. This provides a novel delivery therapeutic system for targeted intervention in DOX-induced chronic heart failure.

II. Main Experimental Methods

This study was conducted at the animal, organ, and molecular levels. The main methods are as follows:

1. Animal model construction

DOX-induced chronic heart failure mice: DOX was intraperitoneally injected once weekly for 5 consecutive weeks to induce myocardial ferroptosis and chronic heart failure;

Biomimetic chiral nanozyme intervention mice: after model establishment, the biomimetic chiral nanozyme was administered via the tail vein;

Sham/solvent control mice: an equal volume of solvent was administered synchronously, without modeling intervention.

2. Core techniques

Template-based synthesis and preparation of nanozymes; small-animal echocardiography for cardiac function detection; combined with cell viability assay, reactive oxygen species (ROS) detection, iron ion content measurement, lipid peroxidation detection, hematoxylin–eosin (HE) staining, Masson staining, immunofluorescence, Western blot, and RNA sequencing (RNA-seq).

3. Detection indicators

Ejection fraction (EF%), fractional shortening (FS%), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV).

4. Echocardiography

Echocardiograms were acquired using a small-animal ultrasound imaging system (VINNO Technology, Suzhou, China).

III. Experimental Results

The figures mainly demonstrate the alleviating effect of the biomimetic chiral nanozyme on DOX-induced myocardial injury. After DOX-induced myocardial injury, rats were treated with the biomimetic chiral nanozyme (Figure 5A). Fluorescence images confirmed that the cell membrane-modified nanozyme could precisely target injured myocardial tissue (Figure 5B). The authors further analyzed the biodistribution of the nanozyme in different organs, showing that the dual-membrane-modified (PM+RM) RD-MM nanozyme could effectively accumulate in the heart (Figure 5C). Meanwhile, the survival of rats in each group was counted (Figure 5D), as well as the changes in heart weight/body weight ratio after treatment (Figure 5E). It was found that after nanozyme treatment, the survival rate of rats was improved, and the HW/BW ratio was significantly increased, suggesting partial recovery of myocardial atrophy and structural degeneration. In particular, the RD-MM group showed the best recovery, indicating that it can protect heart mass and delay the progression of myocardial injury. In addition, the authors evaluated rat cardiac function by echocardiography (Figure 5F) and quantified key cardiac function indicators such as left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) (Figure 5G–J). It was found that after model establishment, the DOX group showed significant decreases in LVEF and LVFS, accompanied by increases in LVEDV and LVESV, indicating obvious impairment of cardiac function. Among all treatment groups, the RD-MM nanozyme exhibited the strongest protective effect, continuously improving LVEF and LVFS and reducing ventricular volume, and this protective effect could be maintained until 3 weeks after treatment.

In summary, from multiple dimensions including targeted distribution, survival rate, heart weight, and echocardiographic function, it was demonstrated that the RD-MM nanozyme (D-type chiral biomimetic nanozyme) can accurately target injured myocardium and significantly alleviate DOX-induced chronic heart failure through multiple mechanisms.

Figure Legends

A: Experimental scheme of biomimetic chiral nanozyme therapy after DOX-induced myocardial injury in rats. DOX was intraperitoneally injected once weekly for 5 consecutive weeks to establish the model, followed by weekly tail vein injection of the nanozyme for 3 consecutive weeks, during which related detections were performed.

B: Fluorescence images of nanozyme targeting injured myocardium before and after cell membrane modification. The fluorescence intensity of RD-MM in the injured heart was 2.1 times that of RD-M, confirming that cell membrane co-modification enhances targeting.

C: Quantitative analysis of Mn element distribution in various organs 24 h after intravenous injection. The accumulation of RD-MM (PM+RM) in the heart was significantly higher than that of the single membrane modification group and the RD-M group, confirming the targeting advantage of dual membrane co-modification.

D: Survival curves of rats in each group. The survival rate of the DOX group was significantly reduced, while that of the RD-MM treatment group was significantly improved, confirming its in vivo therapeutic effect.

E: Quantitative analysis of heart weight/body weight ratio of rats in each group. The ratio was decreased in the DOX group and could be effectively restored in the RD-MM treatment group, suggesting improvement of myocardial atrophy.

F: Echocardiograms of rat hearts in each group. The left ventricular systolic function of the RD-MM group was significantly superior to that of the other treatment groups.

G: Quantitative analysis of left ventricular ejection fraction (LVEF). LVEF in the RD-MM group was significantly higher than that in the RL-MM, RDL-MM, and HMM groups, continuously improving cardiac systolic function.

H: Quantitative analysis of left ventricular fractional shortening (LVFS). LVFS in the RD-MM group was significantly increased, consistent with the LVEF results.

I: Quantitative analysis of left ventricular end-diastolic volume (LVEDV). LVEDV was increased in the DOX group and could be effectively reduced by RD-MM treatment, improving ventricular dilation.

J: Quantitative analysis of left ventricular end-systolic volume (LVESV). LVESV in the RD-MM group was significantly lower than that in the other treatment groups, confirming its inhibitory effect on ventricular remodeling.

IV. Research Conclusion

This study constructed a biomimetic chiral MnO₂ nanozyme that can precisely target DOX-injured myocardial tissue and possesses CAT-like and SOD-like activities. Its core mechanism is to enhance endogenous SOD2 activity by releasing Mn²⁺ while simultaneously delivering Hmox1-targeting siRNA, synergistically inhibiting cardiomyocyte ferroptosis and restoring mitochondrial function, thereby significantly improving cardiac function in rats with chronic heart failure.

V. Publication Information

Title: Chiral metal nanozyme-enabled SOD2 activation and siRNA delivery cooperatively mitigating chronic heart failure

Authors: Zekun Wang, Ruofei Zhang, Yanyu Hu, Qile Song, Xiaoyan Fu, Yifan Wang, Mei Chen, Kelong Fan, Cundong Fan, Dongdong Sun

Journal: Bioactive Materials, April 2026, Volume 58

Original article link: https://www.sciencedirect.com/science/article/pii/S2452199X25005791