Iridium complex-based ferroptosis inducer for cancer sonodynamic therapy

Abstract

Sonodynamic therapy (SDT) offers distinct advantages for deep tumor ablation due to its excellent tissue penetration ability and demonstrates significant clinical potential. However, its therapeutic effectiveness is limited by the sonosensitizer's capacity to produce reactive oxygen species (ROS). In this study, an iridium(III) complex (Ir-1) was designed and evaluated as an potential SDT anticancer agent. Ir-1 exhibits a long triplet excited state lifetime of 2.57 μs and demonstrates efficient ROS generation under ultrasound (US) irradiation, with a rate constant of 0.041 min⁻¹ for 1,3-diphenylisobenzofuran (DPBF) oxidation, which is significantly higher than that of the classic sonosensitizer Ru(bpy)₃Cl₂. Mechanistic studies show that while generating ROS, Ir-1 can deplete intracellular glutathione (GSH), induce lipid peroxidation, and trigger ferroptosis. In mouse tumor models, this complex exhibits significant inhibitory effects on tumor proliferation. This study provides a crucial research foundation for the application of noble metal complexes in tumor SDT.

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Introduction

Cancer ranks among the top causes of death and significantly impacts individuals’ quality of life.¹ Currently, surgery, chemotherapy and radiotherapy serve as the primary first-line clinical treatments for cancer. However, these treatments often result in significant side effects, including tumor recurrence, multi-drug resistance and immune system damage. Consequently, the development of effective and non-invasive treatment strategies has become a major focus in tumor management, particularly for inoperable tumors.² To date, various light-based treatment strategies, including photodynamic therapy (PDT), photothermal therapy (PTT), and microwave therapy, have been introduced to tackle the limitations of conventional treatments.^3–5 Among these, PDT has become a potent minimally invasive modality for tumor treatment, applicable in both basic research and clinical practice.⁶

However, limited light penetration has significantly restricted the application of PDT in vivo, particularly for deep tumors.⁷ Sonodynamic therapy (SDT), a new non-invasive cancer treatment developed from PDT, has garnered significant interest in both research and clinical settings.^8,9 In SDT, ultrasound (US) is used as the excitation source rather than light, producing high levels of cytotoxic reactive oxygen species (ROS) that damage cancer cells.^10,11 Underlying mechanism shows that US irradiation is capable of initiating ultrasonic cavitation, leading to photoacoustic luminescence and thermal decomposition, which activate the sonosensitizer and generate ROS.¹² Due to its exceptional tissue penetration depth (>10 cm), US offers a promising strategy to eradicate deep-seated tumor tissues.^8,13

Sonosensitization efficiency and quantum yield of ROS are crucial requirements for effective SDT.^14,15 Consequently, developing optimal sonosensitizers is essential for advancing SDT. Various inorganic nano-sensitizers have been extensively investigated for SDT in recent years.^16–20 However, their limited biological safety and uncertain compositions have hindered clinical applications. In contrast, small molecule sonosensitizers offer advantages including well-defined structures and facile metabolism, thereby facilitating clinical application.¹⁰ As previously mentioned, the reported sonosensitizers primarily derive from photosensitizers such as porphyrins, phthalocyanines, boron dipyrromethene (BODIPY) and metal complexes.^8,12,21–23 Under US irradiation, these agents are capable of generating ROS and exhibit specific therapeutic effects in SDT. Iridium, a member of the platinum group metals, is recognized for its promising anticancer properties. Its complexes are considered as potential successors to established platinum-based drugs.^24–26 Owing to their stability, ease of synthesis, and adjustable photophysical properties, iridium(III) complexes can be structurally modified to enhance anticancer activity and induce ferroptosis.^27,28 Specifically, the long-lived excited state lifetime of iridium complexes, along with their excellent chemical stability, offers theoretical potential for ROS generation under US. Studies have shown that iridium complexes target various subcellular organelles, including mitochondria, endoplasmic reticulum, lysosomes, Golgi apparatus, and the nucleus.^29,30 These subcellular stress responses induced by iridium complexes generally contribute to subcellular potential loss and ROS production, leading to significant intracellular damage. Lv et al. reported an ionic iridium complex featuring a 4-methyl-2-(thiophen-2-yl)quinolone cyclometalating ligand for SDT.³¹ Therefore, developing iridium-based complexes with simplified structures, easy synthesis, and ligand-bearing capabilities for SDT is highly desirable.

Ferroptosis is a recently discovered form of programmed cell death characterized by its dependence on ROS and two key biochemical features: iron accumulation and lipid peroxidation.^32,33 Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis, utilizes reduced glutathione (GSH) to catalyze the conversion of peroxides to alcohols, thereby reducing lipid peroxides (LPO) and inhibiting ferroptosis.³⁴ Inhibiting GPX4 to induce ferroptosis in tumor cells effectively circumvents apoptosis and reduces drug resistance.³⁵

In this study, we designed and synthesized an iridium-based sonosensitizer (Ir-1) (Scheme 1), which exhibits high sonocytotoxicity and induces tumor ferroptosis. Through analyses of its physical properties, we theoretically confirmed the ROS-generation capability of Ir-1. Under US irradiation, this sonosensitizer efficiently produces ROS and against 4T1 breast cancer cells. Mechanistic investigations reveal that Ir-1 promotes LPO accumulation and downregulates GPX4 expression under US exposure, thereby inducing ferroptosis in cancer cells. Notably, Ir-1 markedly inhibits tumor growth under US irradiation while maintaining favorable biocompatibility, highlighting its promising potential for SDT in tumor treatment.

Scheme 1 Schematic illustration of iridium(III) complex for ferroptosis-augmented sonodynamic therapy.

Results and discussion

Synthesis and characterization

The synthetic route for the iridium complex Ir-1 is illustrated in Fig. 1a. The ligand L1 was synthesized with high yield via a palladium-catalyzed Suzuki coupling reaction. The complex Ir-1 was prepared by reacting [Ir(C^N)₂Cl]₂ with the auxiliary ligand 5-hydroxypicolinic acid. In synthesizing neutral iridium complexes, we employed dichloromethane and ethanol as solvents. To enhance the yield, we directly removed the solvents via vacuum evaporation, obtaining the crude product without extraction and drying procedures. Following column chromatography purification (dichloromethane : methanol = 20 : 1, v/v), the red product (yield: 43%) was obtained. The target iridium complex Ir-1 was obtained by grinding with dichloromethane because of its limited solubility in that solvent. The chemical structure of Ir-1 was confirmed by nuclear magnetic resonance spectroscopy (¹H NMR and ¹³C NMR) (Fig. S2 and S3†) and high-resolution mass spectrometry (HRMS) (Fig. S4†).

Fig. 1 Characterization and ROS-generating properties of Ir-1. (a) Synthetic route for Ir-1. (b) Absorption and photoluminescence spectra of Ir-1 (10 μM) in CH₂Cl₂ at 298 K (λ_ex = 400 nm). (c) Cyclic voltammetry graph for Ir-1 (2 mM, in CH₃CN). (d) Transient absorption spectra of Ir-1 (10 μM) in N₂-purged dimethyl sulfoxide (DMSO). (e) The absorption spectra of Ir-1 under different US irradiation times (2.5 W cm⁻²). (f) Absorption ratio of 288 nm/472 nm for Ir-1 under different US irradiation times (2.5 W cm⁻²). (g) Absorbance attenuation of DPBF (10 μM, in N,N-dimethylformamide, DMF) by ROS generation in the presence of Ir-1 (10 μM) following various irradiation durations (2.5 W cm⁻²). (h) Time-dependent absorption change at 410 nm. (i) Rate constant for 1,3-diphenylisobenzofuran (DPBF) decomposition at 410 nm in (g). (j) The ¹O₂ by 4-oxo-2,2,6,6-tetramethylpiperidine (TEMP) and Ir-1 upon US irradiation (2.5 W cm⁻², 5 min) detected by electron spin resonance (ESR) spectroscopy.

Photophysical properties and potential of Ir-1 as sonosensitizer

The capacity for ROS production is a crucial factor in the efficiency of sonosensitizers. Under US conditions, the sonosensitizers transition from the ground state (S₀) to the excited singlet state (S₁). The small energy gap (ΔE_st) between the singlet (S₁) and triplet (T₁) excited states facilitate the intersystem crossing (ISC) process, enabling the transition to the triplet excited state (T₁). This triplet excited state (T₁) subsequently reacts with oxygen to produce ROS.³⁶ Therefore, ROS production primarily depends on the degree of energy overlap with O₂ and the properties of the triple excited state of the sonosensitizers.

Next, we investigated the absorption and emission spectra of Ir-1 (Fig. 1b and S5†). The choice of polar solvents had no significant effect on the positions of the absorption peaks of these complexes. A strong absorption band near 300 nm is primarily attributed to a ¹π–π* transition in the ligand.³⁷ The weak absorption peaks between 400 and 500 nm are primarily due to charge transfer from metal to ligand (¹MLCT) and from ligand to ligand (¹LLCT).^38–40 A broad absorption band was observed in the range of 409–509 nm, with the corresponding absorption coefficient (ε = 0.68 × 10⁴ M⁻¹ cm⁻¹) higher than that of typical iridium complex photosensitizers (ε = 0.12 × 10⁴ M⁻¹ cm⁻¹) reported in the literature.^41,42 This higher coefficient facilitates enhanced sensitization efficiency under laser or US irradiation.

To further verify the possibility of ROS generation, cyclic voltammetry (CV) was conducted within the scan range, revealing double oxidation peaks of Ir-1 at 1.016 and 1.590 V were observed (Fig. 1c and Table S1†). This observation is consistent with the initial oxidation of the benzothiophene portion followed by the oxidation of the metal center (Ir³⁺/Ir⁴⁺).⁴³ This aligns with the guideline for the oxidation potential of an effective sonosensitizer (1.10 V vs. saturated calomel electrode, corresponding to 1.14 V for Ag/AgCl).⁴⁴

The photophysical properties of Ir-1 complex were further investigated using time-dependent density functional theory (DFT). As illustrated in Fig. S6,† the HOMO electron cloud of Ir-1 is predominantly located on the L1 ligand, whereas the LUMO is associated with the secondary ligand. The effective separation of HOMO and LUMO in Ir-1 indicates that ΔE_st is small, promoting an efficient ISC process. Due to the small ΔE_st of Ir-1, most S₁ excitons are converted to T₁ states, promoting the generation of ROS.

Matching energy levels between the triplet excited state of the sonosensitizer and the single excited state of O₂ is essential for effective energy transfer. O₂ has two single excited states with absorption wavelengths of 762 and 1268 nm,⁴⁴ indicating that the lowest triplet excited state energy of the sonosensitizer should exceed 762 nm (i.e. 1.63 e V). The complex Ir-1 (λ_max = 606 nm) (Fig. 1b) has a triplet excited state energy level (E_T = 2.13 eV), suitable for efficiently transferring energy to ground state O₂.

The characteristics of the triplet excited state were further investigated. The nanosecond time-resolved transient absorption (TA) spectrum displays excited state absorption bands at 400 and 700 nm (Fig. 1d and S7†), indicating the formation of the triplet excited state. Additionally, the triplet excited state has a lifetime of 2.57 μs, enabling a photoinduced energy transfer process to occur after laser activation.⁴⁵ In the presence of O₂, the phosphorescence intensity of Ir-1 is significantly diminished, indicating that Ir-1 interacts more strongly with the excited state of O₂ and demonstrates an enhanced capability to generate ROS (Fig. S8†).

ROS generation under US irradiation

To assess the ultrasonic stability and chemical stability of Ir-1, absorption spectra were measured at varying ultrasonic durations and pH values, and the thermal stability of the complex was also verified (Fig. 1e, f and S9, S10†). The mass fraction of the complex did not change significantly before 400 °C, indicating good thermal stability. After ultrasonic treatment for 10 minutes at a power of 2.5 W cm⁻², the absorption of Ir-1 did not obviously decrease, indicating good stability. The absorption intensity of Ir-1 remained stable within a pH range of 4–9, indicating its stability within the physiological pH range.

Ru(bpy)₃Cl₂ has been identified as an effective sonosensitizer in prior studies.⁸ Consequently, we utilized ROS indicator 1,3-diphenylisobenzofuran (DPBF) to identify and measure ROS. In Fig. 1g, as irradiation time increased, the characteristic absorption peak of DPBF near 410 nm progressively diminished in the presence of Ir-1. In presence of both Ir-1 and US irradiation, the rate constant of DPBF oxidation was 0.041 min⁻¹, compared to Ru(bpy)₃Cl₂ (Fig. 1h, I and S11†). In the presence of Ir-1, the characteristic absorption peak of DPBF decreased more markedly. The rate constant of DPBF oxidation by Ru(bpy)₃Cl₂ under US irradiation was 0.035 min⁻¹, indicating that Ir-1 generates more ROS under US irradiation. To further investigate this phenomenon, the degradation of DPBF was found to be consistent across different ultrasonic power levels. This enhanced degradation behavior of DPBF may be attributed to the increased cavitation intensity induced by US, resulting in greater ROS generation by Ir-1 (Fig. S12†).⁴⁶ To validate the generated ROS, we utilized electron spin resonance (ESR) spectroscopy for detection. The scavenger agent used in this process was 2,2,6,6-tetramethylpiperidine (TEMP). The ESR data revealed a set of clear peaks with an intensity ratio of 1 : 1 : 1, located at approximately 3500 G. Furthermore, 5,5-dimethyl-1-pyrrolidinone-N-oxide (DMPO) was employed as an ˙OH scavenger. No signals of DMPO/˙OH adducts were observed in the solutions of Ir-1 and DMPO in the absence and presence of US irradiation, indicating that Ir-1 produced ¹O₂ rather than ˙OH under the irradiation of US (Fig. 1j and S13†).

Sono-toxicity in vitro

In order to evaluate therapeutic effect of Ir-1 on 4T1 cells under US conditions, we utilized Cell Counting Kit-8 (CCK-8) to assess the proliferation ability of Ir-1 on 4T1 cells. After incubation for 24 and 48 hours, the cell viability was 86.1% and 86.4%, respectively, at Ir-1 concentrations of 50 μM, demonstrating no significant inhibition of cell proliferation. This suggests that Ir-1 exhibits low cytotoxicity (Fig. 2a). However, when US was applied, cell viability decreased significantly with increasing concentrations of Ir-1 and longer US duration, resulting in a cell viability of 17.1% (Fig. 2b). Ir-1 demonstrated significant dose-dependent sonocytotoxicity, with an IC₅₀ (half maximal inhibitory concentration) value of 27.87 μM (Fig. 2c). IC₅₀ value was higher than that of traditionally reported small molecule ruthenium complex photosensitizers.⁴⁷ We evaluated the cytotoxicity of normal 293T cells under both ultrasonic and non-ultrasonic conditions (Fig. 2d and g). Without US, Ir-1 showed negligible cytotoxicity toward 293T cells across all tested concentrations. Under US irradiation, Ir-1 exhibited some cytotoxic effects on normal cells, but these were significantly weaker than those observed in 4T1 cancer cells, demonstrating its preferential toxicity toward tumor cells. Notably, Ir-1 also induced cytotoxicity in A549 and HepG2 cancer cells under US exposure (Fig. 2e, f, h and i), highlighting its potential for SDT.

Fig. 2 Cytotoxicity of Ir-1 in different cell lines under varying conditions. (a) 4T1 cells treated with Ir-1 at different concentrations for 24 h and 48 h. (b) 4T1 cells treated with Ir-1 at different concentrations and irradiated with US (0.7 W cm⁻², 5 min) for different times. (c) Sono-toxicity IC₅₀ fitting curve of Ir-1. (d) 293T, (e) A549, and (f) HepG2 cells treated with Ir-1 at different concentrations for 24 h. (g) 293T, (h) A549, and (i) HepG2 cells treated with Ir-1 at different concentrations and irradiated with US (0.7 W cm⁻², 5 min).

In cells, 2,7-dichlorofluorescein (DCFH-DA) was used to monitor ROS generation, along with the calcein-AM/propidium iodide (PI) kit (live cells, green; dead cells, red) to verify the cytotoxicity of Ir-1 triggered by US. Compared to the control group, the US alone group and the Ir-1 alone group, the ROS content in the Ir-1 + US group significantly increased (Fig. 3a and b), indicating that Ir-1 can generate ROS under US irradiation. Live/dead cell staining revealed that the control group, the US alone group and the Ir-1 alone group displayed strong green fluorescence (live cells), indicating that physiological activity of 4T1 cells is good. However, Ir-1 + US group exhibited prominent red fluorescence (Fig. 3a and c), indicating that a significant amount of ROS was produced, activating various cell death pathways. Consequently, emergence of ROS has an impact on cell viability, disrupts the redox balance of cells and leads to cell death.⁴⁸

Fig. 3 (a) Fluorescence images and (b) Relative DCF intensities of 4T1 cells under various treatments (0.7 W cm⁻², 5 min). (c) Corresponding live/dead ratios of 4T1 cells after various treatments (0.7 W cm⁻², 5 min).

Ferroptosis mechanism

Subsequently, we investigated the mechanism by which Ir-1 induces tumor cell death under US irradiation. Ferroptosis is an iron-dependent form of cell death caused by excessive lipid oxidation. A key feature of ferroptosis is that after the antioxidant capacity of the cell is compromised, phospholipids and polyunsaturated fatty acids undergo peroxidation on the cell membrane, leading to cell membrane damage and ferroptosis. GPX4 is essential for neutralizing LPO through a GSH-dependent mechanism, Inhibiting GPX4 induces ferroptosis.⁴⁹ Therefore, we assessed expression of GPX4 in cells by western blot (WB). As shown in Fig. 4a, Ir-1 will not affect the expression of GPX4 in cells without US treatment. However, under US treatment, Ir-1 significantly decreased expression of GPX4 in 4T1 cancer cells. This indicates that Ir-1, as a potential GPX4 inhibitor, exerts antitumor effects by inducing ferroptosis.

Fig. 4 Impact of Ir-1 on expression of GPX4 in 4T1 cells analyzed by (a) WB. (b) Confocal laser scanning microscope images of C11-BODIPY-dye-stained 4T1 cells treated with Ir-1. (c) MDA levels in 4T1 cells after different treatments. (d) Fluorescence images and (e) intensities of cellular fluorescence level in 4T1 cells after varying treatments. (f) GSH levels in 4T1 cells under different groups (0.7 W cm⁻², 5 min; n = 3). (g) TEM images of 4T1 cells under different treatment conditions (0.7 W cm⁻², 5 min). The statistical significance was indicated as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

To further validate this conjecture, we directly employed the specific probe C11-BODIPY to detect LPO levels in 4T1 cells.⁵⁰ Ir-1 was inactive in the absence of US, displaying equivalent red fluorescence intensity compared to the control group. However, after US irradiation, Ir-1 significantly elevated LPO levels (Fig. 4b). Additionally, malondialdehyde (MDA), as a product of LPO and a contributor to cellular damage induced by oxidative stress,⁵¹ was increased in a concentration-dependent manner at the intracellular level in the presence of Ir-1 and US (Fig. 4c and S14†). These findings demonstrate that Ir-1 effectively promotes the accumulation of LPO in 4T1 cells and disrupts the redox balance, potentially inducing ferroptosis and inhibiting tumors.

To further confirm ferroptosis, mitochondrial damage was investigated as a key indicator at the organelle level. The mitochondrial membrane potential (MMP, ΔΨ_m) was monitored by JC-1 staining.^52,53 Incubation of 4T1 cells with Ir-1 and US irradiation resulted in depolarization of MMP, as evidenced by a decrease in the red fluorescence of JC-1 aggregates and an increase in the green fluorescence of JC-1 monomers (Fig. 4d and e). Detection results showed a significant increase in Fe²⁺ levels in the Ir-1 + US group (S15†), indicating iron overload occurred during treatment, which triggered ferroptosis. Additionally, GSH content in 4T1 cells was measured (Fig. 4f and S16†). Results confirmed a marked decrease in intracellular GSH levels after treatment, while pre-treatment with ferroptosis inhibitors restored GSH levels. This demonstrated that ferroptosis was induced by ROS generated from Ir-1 + US treatment combined with iron overload.

Transmission electron microscopy (TEM) was used to analyze mitochondrial microstructure under different treatment conditions (Fig. 4g). Compared to other groups, cells treated with Ir-1 + US exhibited distinct mitochondrial damage, including structural and morphological abnormalities such as mitochondrial atrophy, increased membrane density, and cristae destruction. These findings indicate that mitochondrial dysfunction characteristics are closely associated with ferroptosis activation.²⁷ Together with prior results, this confirms that Ir-1 + US can activate ferroptosis. Thus, ¹O₂ generated by SDT effectively inhibits GPX4 expression, promotes LPO accumulation, and ultimately induces ferroptosis.

Biosafety in vivo

Before assessing the therapeutic effect of Ir-1 in treating living tumors, its biological safety must be evaluated. In vitro hemolysis test demonstrated that hemolysis rates in each group were below 5.0%, indicating that Ir-1 has good blood compatibility within a specific concentration range (Fig. S17†). We analyzed the effects of Ir-1 on routine blood indicators and major organs 21 days after its intravenous injection. No significant differences in blood indicators were observed between mice injected with Ir-1 and those injected with phosphate buffered saline (PBS) (Fig. S18†), suggesting that Ir-1 does not affect various blood cells. Hematoxylin–Eosin (H&E) staining images of organ sections do not show any obvious morphological changes (Fig. S19†). These results indicate that Ir-1 demonstrates good biocompatibility.

In vivo sonodynamic therapy

Due to the fact that Ir-1 exhibits sonocytotoxicity, we further investigated in vivo anti-tumor efficacy in a 4T1 tumor-bearing mice model. The treatment methods are illustrated in Fig. 5a. Based on the weight condition of control group mice, there was no significant difference in weight of the other three groups. This indicates that treatment was quite safe in terms of biological safety (Fig. 5b). Tumor volumes in control group, US group with Ir-1 alone group increased significantly. In contrast, mice in the Ir-1 combined with US group exhibited a markedly greater inhibitory effect on tumor proliferation, with the slope of the curve being negatively correlated to that of the control group, and this difference was statistically significant (Fig. 5c and f–i). Based on the treatment outcomes of digital photos of tumors, Ir-1 + US group demonstrated the strongest anti-tumor effect (Fig. 5d and e), confirming the superior therapeutic advantages of SDT.

Fig. 5 (a) Schematic diagram of in vivo therapeutic protocol. (b) Changes of body weight under treatments. (c) The relative tumor volume of different groups after different treatments (n = 3). (d and e) Tumors weight and photos of tumors with treatment. (f–i) Tumor growth curves of four treatment groups. (j) H&E staining images of tumor sections in each treatment group and fluorescence images of 4T1 cells under various treatments. The statistical significance was indicated as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

The therapeutic efficacy of US treatment combined with Ir-1 was further evaluated using H&E staining. When compared to other treatment groups, a significantly broader area of apoptotic and necrotic tumor cells was revealed by H&E analysis in the Ir-1 + US group (Fig. 5j). Besides, a notable reduction in fluorescence intensity of tumor tissues was observed in the Ir-1 + US group, indicating a substantial downregulation of GPX4 expression (Fig. S20 and S21†), which was aligned with the results obtained from WB assays. These findings are collectively demonstrated to indicate that antitumor activity is possessed by Ir-1.

Conclusions

We herein report an iridium complex-based sonosensitizer that induces ferroptosis in tumor cells for cancer therapy. Theoretical analyses, supported by its favorable oxidation potential and energy level alignment with O₂, confirmed that Ir-1 efficiently generates triplet excited states and transfers energy to O₂. With a triplet excited state lifetime of 2.57 μs, Ir-1 exhibits exceptional SDT performance due to its prolonged excited-state persistence. In vitro studies demonstrated robust ROS generation by Ir-1 under US irradiation, accompanied by significant sonocytotoxicity (IC₅₀: 27.87 μM). Mechanistic investigations further validated US-activated Ir-1-induced ferroptosis through comprehensive analyses of intracellular ROS, MDA, LPO levels, and MMP disruption. Notably, Ir-1 showed potent antitumor efficacy while maintaining biological safety, highlighting its clinical translatability for SDT. This work deepens our understanding of iridium-based sonosensitizer mechanisms and provides a foundational framework for designing transition metal-based sonosensitizers.

Author contributions

Guihong Ren: methodology, data curation, writing – original draft; Qingxuan Meng: investigation; Panpan Li: data curation; Chenyi Wang: conceptualization; Chenglong Wu: conceptualization; Rui Liu: conceptualization, writing – review and editing, supervision; Yuhao Li: funding acquisition, supervision, writing – review and editing; Senqiang Zhu: funding acquisition, supervision; Hongjun Zhu: funding acquisition, supervision.

Data availability

All relevant data are presented in the main text and ESI.† The ESI† contains detailed descriptions of the experimental proce dures, product characterization data, NMR spectra, HRMS data, DFT calculation, stability data, ROS measurements, ESR spectra, hemocompatibility.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

The authors greatly acknowledge the National Key R&D Program of China (2023YFA0913600), Natural Science Foundation of Jiangsu Province (BK20220351), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (22KJB150027), and the Natural Science Foundation of Shanghai (24ZR1453600). The computational resources generously provided by the High Performance Computing Center of Nanjing Tech University are greatly appreciated. Scheme 1 was drawn using Figdraw.

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Footnote

† Electronic supplementary information (ESI) available: Additional spectroscopic and imaging data. See DOI: https://doi.org/10.1039/d5qi00746a

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