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. 2026 Aug 17;11(34):50992–51003. doi: 10.1021/acsomega.6c02956

Targeted Catalytic Anti-Inflammatory and Antioxidant Therapy for Aortic Dissection Using Biomimetic Nanomaterials

Hongwei Ge 1, Jun Wang 1, Ziyang Li 1, Dongmei Di 1, Weibin Huang 1, Xin Wang 1, Yiming Huang 1, Xiaoying Zhang 1,*
PMCID: PMC13625157  PMID: 42819177

Abstract

Aortic dissection (AD) is a life-threatening cardiovascular disease with an extremely high mortality rate. Excessive reactive oxygen species (ROS) production and inflammatory responses in diseased vascular regions are central drivers of AD pathogenesis, leading to destruction of the aortic wall structure and fatal hemorrhage. However, conventional clinical therapies for AD cannot effectively eliminate excessive ROS at lesion sites while simultaneously exerting anti-inflammatory effects. To address these limitations, we developed a biomimetic, inflammation-targeting nanoparticle, ZIF-8@Res@PEG-FA (ZRF), to attenuate AD progression through potent antioxidant and anti-inflammatory interventions. ZRF is constructed with ZIF-8 as the core carrier, loaded with the antioxidant and anti-inflammatory agent resveratrol, and surface-modified with PEG-folic acid (PEG-FA). This nanoparticle enhances resveratrol bioavailability and leverages the inflammation-targeting capability of folic acid to preferentially accumulate in AD lesions. Under mildly acidic conditions, ZRF rapidly degrades and efficiently scavenges ROS, disrupting the oxidative stress–inflammation vicious cycle and promoting the polarization of pro-inflammatory M1 macrophages toward the anti-inflammatory M2 phenotype. Notably, ZRF also preserves the contractile phenotype of vascular smooth muscle cells (VSMCs), maintains extracellular matrix stability, and thereby delays AD progression. This study presents a promising therapeutic strategy for aortic dissection and other inflammatory vascular diseases.

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1. Introduction

Acute aortic dissection (AD) is a catastrophic cardiovascular emergency with sudden onset and extremely high mortality. It is initiated by a tear in the aortic intima, allowing blood to enter the medial layer and form a false lumen that separates the aortic wall layers. Without timely intervention, rupture of the adventitia can cause massive hemorrhage, and mortality increases by approximately 1% per hour after onset. Even among patients who survive the acute phase, AD is often accompanied by severe complications that markedly impair quality of life and long-term prognosis. Recent advances in molecular pathology have identified oxidative stress and inflammatory responses as central drivers of AD initiation and progression. Risk factors such as hypertension increase mechanical stress on the aortic wall, leading to excessive production of reactive oxygen species (ROS) and triggering oxidative stress. This process damages biomacromolecules, promotes apoptosis of vascular smooth muscle cells (VSMCs), and accelerates extracellular matrix (ECM) degradation, thereby compromising the structural integrity of the aortic media and creating a pathological substrate for AD development. Despite these insights, current clinical management of AD still relies primarily on surgical repairincluding open graft replacement and minimally invasive endovascular stent-graft implantationalongside strict control of blood pressure and heart rate as supportive therapy. Specific pharmacological interventions that directly target oxidative stress and inflammation, the core pathological mechanisms of AD, remain scarce. Although several systemically administered agents with antioxidant or anti-inflammatory properties (e.g., N-acetylcysteine and coenzyme Q10) have been approved for related conditions, their use in AD is limited. These include poor lesion-specific targeting, which necessitates high systemic doses and increases the risk of off-target toxicity; unfavorable pharmacokinetic properties, such as low stability, a short half-life, and limited bioavailability; and insufficient efficacy of single-mechanism drugs given the complex, multipathway pathology of AD. In light of these challenges, precise and efficient antioxidant and anti-inflammatory interventions targeting diseased vascular regions during the acute phase of AD have emerged as a highly promising therapeutic strategy. By eliminating excessive ROS and suppressing uncontrolled inflammation, such approaches may stabilize the aortic wall structure and effectively halt disease progression.

Resveratrol (Res) is a natural polyphenol with potent antioxidant and anti-inflammatory properties. It exerts biological effects through multitarget and multipathway regulation, rather than merely eliminating free radicals directly. Res can enhance the activity of endogenous antioxidant enzymes, including SOD, GSH-Px, and CAT, thereby strengthening the cellular antioxidant defense system. Nevertheless, poor water solubility, low bioavailability, and dose-dependent toxicity severely limit its clinical application. Accordingly, optimizing conventional administration strategies for Res has significant research value and application prospects.

ZIF-8 is a metal–organic framework (MOF) composed of Zn2+ ions coordinated to 2-methylimidazole, offering several unique advantages as a biomimetic drug carrier nanomedicine. First, its pH-responsive degradability enables site-specific drug release in AD lesions, which are characterized by a mildly acidic microenvironment resulting from ischemia and inflammatory cell infiltration, thereby minimizing off-target effects. Second, ZIF-8 exhibits excellent drug-loading capacity owing to its large specific surface area, enabling efficient encapsulation of various therapeutic molecules. Third, ZIF-8 demonstrates favorable biocompatibility and biodegradability because its degradation productsZn2+ and imidazoleare well tolerated at appropriate concentrations and can be metabolized in vivo. Moreover, Zn2+ has been reported to promote angiogenesis, further supporting its biosafety profile. Fourth, ZIF-8 enables facile surface functionalization, enabling versatile chemical modifications. ZIF-8 exhibits favorable biocompatibility, high drug-loading capacity, and pH-responsive drug release. ZIF-8 encapsulation efficiently overcomes the shortcomings of resveratrol (Res), including poor water solubility, low bioavailability, and dose-dependent toxicity. Therefore, ZIF-8 serves as an ideal delivery vehicle for Res in this study, greatly facilitating the clinical translation and practical application of Res.

Based on these properties and the pathological characteristics of AD, we designed a ZIF-8–based biomimetic nanoparticle system. PEGylation of ZIF-8 was used to enhance biocompatibility, prevent rapid clearance by the mononuclear phagocyte system (MPS), and prolong systemic circulation. Subsequently, an active targeting strategy was introduced. Previous studies using single-cell RNA sequencing have quantitatively demonstrated that macrophages are preferentially enriched in AD lesions compared with normal tissues, highlighting the prominent overexpression of pro-inflammatory M1 macrophages during disease progression. Folic acid (FA), a natural ligand for the folate receptor β (FRβ), has high affinity for M1 macrophages and was therefore selected to confer active targeting capability. This design overcomes the challenge of insufficient drug accumulation in the aortic wall caused by rapid blood flow, thereby improving therapeutic efficacy. Ensuring high lesion-specific targeting is essential to enhance the effectiveness and safety of nanotherapeutic strategies for aortic dissection.

Therefore, given the unmet clinical needs in aortic dissection (AD) and the distinctive advantages of ZIF-8 carriers and biomimetic approaches, we propose developing a biomimetic nanoparticle system that targets vascular inflammatory lesions to scavenge reactive oxygen species (ROS) and suppress inflammation, thereby offering a novel therapeutic strategy for AD. As illustrated in Scheme , a core–shell biomimetic nanoparticle, designated ZIF-8@Res@PEG-FA (ZRF), was constructed using zeolitic imidazolate framework-8 (ZIF-8) nanoparticles as the core carrier, loaded with the anti-inflammatory and antioxidant agent resveratrol, and surface-modified with PEG–folic acid (PEG-FA). This nanoplatform enhances resveratrol’s limited absorption and low bioavailability and exploits folic acid’s inflammation-targeting capability to preferentially accumulate in aortic walls affected by AD. Under mildly acidic conditions, the ZIF-8 core rapidly degrades, enabling site-specific release of Zn2+which contributes to angiogenesisand resveratrol. Through this coordinated release, ZRF efficiently scavenges excess ROS, disrupts the oxidative stress–inflammation vicious cycle, and promotes the polarization of pro-inflammatory M1 macrophages toward the anti-inflammatory M2 phenotype, thereby alleviating aortic inflammation. In addition, ZRF facilitates the restoration of vascular smooth muscle cells (VSMCs) from an inflammation-induced synthetic phenotype to the physiological contractile phenotype, protecting VSMCs, preserving extracellular matrix (ECM) stability, and ultimately delaying AD progression. Collectively, this work provides a potential conceptual framework and therapeutic avenue for treating aortic dissection.

1. Synthesis of ZIF-8@RES@PEG-FA Biomimetic Nanoparticles and Their Application in Anti-Inflammatory and Antioxidant Therapy for Aortic Dissection (AD).

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2. Materials and Methods

2.1. Preparation of ZIF-8@Res@PEG-FA Nanoparticles

ZIF-8 nanoparticles were synthesized by mixing zinc nitrate hexahydrate and 2-methylimidazole (molar ratio 1:4) in methanol, followed by stirring for 1.5 h and aging at room temperature for 24 h. The precipitate was collected by centrifugation, washed with methanol, and vacuum-dried. Resveratrol (Res) was subsequently loaded into ZIF-8 by adsorption in methanol under stirring for 12 h to obtain ZIF-8@Res. The optimal drug-loading ratio was determined by varying the initial Res concentration. PEG-FA was conjugated by incubating ZIF-8@Res with PEG-FA (1:1, w/w) in deionized water for 48 h in the dark. The resulting ZIF-8@Res@PEG-FA nanoparticles were purified by centrifugation, washed with deionized water, and vacuum-dried before further use.

2.2. Cytocompatibility Assay

The cytocompatibility of BAN, ZIF-8@Res, ZIF-8@Res@PEG-FA, and blank PEG-FA@ZIF-8 was evaluated in 293T cells, HUVECs, and VSMCs using the CCK-8 assay after 12 and 24 h of incubation. Cell viability was calculated according to the manufacturer’s protocol.

2.3. Cellular Uptake

RAW264.7 macrophages were stimulated with lipopolysaccharide (LPS) to induce M1 polarization. Cellular uptake of Cy5.5-labeled ZIF-8@Res and ZIF-8@Res@PEG-FA was examined in M0 and M1 macrophages by confocal laser scanning microscopy (CLSM).

2.4. Intracellular ROS Detection

LPS-induced M1 macrophages were incubated with ZIF-8, Res, ZIF-8@Res, or ZIF-8@Res@PEG-FA. Intracellular reactive oxygen species (ROS) levels were assessed using the DCFH-DA fluorescent probe and visualized by CLSM.

2.5. Immunofluorescence Staining

Macrophages were fixed, blocked, and incubated with primary antibodies against CD80 and CD206, followed by fluorophore-conjugated secondary antibodies. Cell nuclei were counterstained with DAPI, and fluorescence images were obtained by CLSM.

2.6. Cell Migration Assay

The migration of VSMCs was evaluated using a scratch wound assay. Wound closure was quantified from microscopic images acquired immediately after scratching and after 24 h of treatment.

2.7. Tube Formation Assay

HUVECs were seeded onto growth factor-reduced Matrigel and treated as indicated. Capillary-like structures were imaged after 24 h, and tube formation was quantitatively analyzed.

2.8. Hemolysis Assay

Hemocompatibility was evaluated using mouse erythrocytes. Hemolysis was quantified by measuring the absorbance of the supernatant at 414 nm, with phosphate-buffered saline and deionized water serving as negative and positive controls, respectively.

2.9. In Vivo Therapeutic Evaluation

An aortic dissection model was established in C57BL/6J mice by β-aminopropionitrile (BAPN) administration. Animals received intravenous injections of PBS or ZIF-8@Res@PEG-FA (50 mg kg–1). Aortic diameter was monitored by ultrasonography, followed by histological assessment using hematoxylin and eosin (H&E), elastic Van Gieson (EVG), Masson’s trichrome, α-SMA, osteopontin (OPN), and CD86/CD206 immunofluorescence staining.

3. Results and Discussion

3.1. Synthesis and Characterization of Biomimetic Nanomaterial

The main paragraph text follows directly here. The morphology of the nanomaterials was examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) (Figure S1). TEM images of ZIF-8 (Figure A a–b), ZIF-8@Res (Figure A c–d), and ZIF-8@Res@PEG-FA (Figure A e–f) show that the synthesized nanoparticles were well dispersed, with average diameters of 96.52, 108.75, and 125.73 nm, respectively. TEM observations revealed that bare ZIF-8, ZIF-8@Res, and ZRF exhibited a rhombic dodecahedral morphology, consistent with previous reports, indicating that drug loading did not disrupt the intrinsic ZIF-8 framework. Compared with the well-defined polyhedral structure of ZIF-8, ZIF-8@Res@PEG-FA displayed blurred edges and a more spherical morphology, with a thin film-like surface layer attributed to PEG-FA, confirming successful drug loading and surface modification. The hydrodynamic diameters of ZIF-8, ZIF-8@Res, and ZIF-8@Res@PEG-FA were measured by dynamic light scattering (DLS) (Figures B and S2–S3) and were 101 ± 2.9 nm, 131.13 ± 1.19 nm, and 176 ± 8.1 nm, respectively. All samples exhibited narrow size distributions and good aqueous dispersibility. The significantly larger hydrodynamic size of ZIF-8@Res@PEG-FA relative to ZIF-8 further confirms successful resveratrol loading and PEG-FA modification. The slightly larger sizes measured by DLS relative to TEM are attributed to nanoparticle swelling in aqueous solution, whereas partial shrinkage occurs during drying for TEM imaging. Zeta potential analysis showed values of 18.47 ± 1.4 mV for ZIF-8, −26.03 ± 1.58 mV for resveratrol, – 23.83 ± 1.1 mV for ZIF-8@Res, and – 20.83 ± 1.8 mV for ZIF-8@Res@PEG-FA (Figure C). The negative surface charge after drug loading is attributed to the multiple phenolic hydroxyl groups of resveratrol, while carboxyl groups in PEG-FA maintain a negative zeta potential after surface modification. UV–visible spectroscopy showed that free resveratrol exhibited characteristic absorption peaks at 228 and 306 nm. In contrast, the intensity of the 306 nm peak gradually decreased in ZIF-8@Res and ZRF, indicating successful encapsulation of resveratrol within the ZIF-8 framework (Figure D). X-ray diffraction (XRD) analysis further confirmed drug loading. The crystalline structure of ZIF-8 was consistent with previous reports, and both ZIF-8@Res and ZIF-8@Res@PEG-FA retained the characteristic diffraction pattern of ZIF-8, indicating that drug loading did not significantly disrupt the framework. Compared with ZIF-8@Res, ZIF-8@Res@PEG-FA showed partial masking of low-angle diffraction peaks due to PEG-FA coverage, confirming surface modification (Figure E). Fourier transform infrared (FTIR) spectroscopy further confirmed the synthesis of ZIF-8@Res@PEG-FA. The FTIR spectrum of ZRF showed distinct stretching vibrations for phenolic hydroxyl (O–H), carbonyl (CO), and ether (C–O–C) groups (Figure F), confirming successful incorporation of resveratrol and PEG-FA. Finally, the porosity of ZIF-8@Res@PEG-FA was evaluated using the Brunauer–Emmett–Teller (BET) method, with ZIF-8 as a control (Figure G). Both materials exhibited typical nitrogen adsorption–desorption isotherms characteristic of microporous structures. However, ZRF showed reduced nitrogen adsorption capacity due to pore filling by the loaded drug. The specific surface areas of ZIF-8 and ZIF-8@Res@PEG-FA were 1293 m2/g and 432 m2/g, respectively. The sharply reduced specific surface area of ZIF-8@RES (432 m2/g) is mainly attributed to the pore-filling effect. The loaded RES molecules are encapsulated within the internal porous structure of ZIF-8, which occupies the pore channels and void spaces of the carrier. Meanwhile, a slight surface coating also exists on the outer surface of ZIF-8, which further leads to the obvious decline of the BET surface area. The marked decrease in surface area after drug loading and PEG-FA modification further demonstrates that the pores of ZIF-8 were effectively occupied, confirming successful resveratrol loading and surface functionalization with PEG-FA for biomimetic targeting.

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Characterization of ZIF-8@RES@PEG-FA.(A) SEM images of ZIF-8 (a, Scale bar: 500 nm), ZIF-8@RES (c, Scale bar: 500 nm) and ZIF-8@RES@PEG-FA (e, Scale bar: 500 nm); TEM images of ZIF-8 (b, Scale bar: 200 nm), ZIF-8@RES (d, Scale bar: 200 nm) and ZIF-8@RES@PEG-FA (f, Scale bar: 200 nm). (B) DLS size distribution of ZIF-8, ZIF-8@RES, and ZIF-8@RES@PEG-FA. (C) Zeta potential of ZIF-8, RES, ZIF-8@RES and ZIF-8@RES@PEG-FA. (D)­UV absorption spectra of ZIF-8, RES, PEG-FA, ZIF-8@RES, and ZIF-8@RES@PEG-FA. (E) XRD patterns of ZIF-8, PEG-FA, ZIF-8@RES and ZIF-8@RES@PEG-FA. (F) FTIR spectra of as-prepared ZIF-8, RES, PEG-FA, ZIF-8@RES, and ZIF-8@RES@PEG-FA. (G) N2 adsorption–desorption isotherms of as-prepared ZIF-8 and ZIF-8@RES@PEG-FA. Data are presented as mean ± SD (n = 3).

3.2. In Vitro Cell Experiments

3.2.1. In Vitro Drug Release and Cytotoxicity

After successful drug loading, efficient release of the therapeutic agent from the carrier at the target lesion site after systemic circulation is essential. ZIF-8 is stable under neutral conditions but readily degrades in acidic environments. Given that AD lesions exhibit a mildly acidic microenvironment due to ischemia and inflammatory cell infiltration, this property of ZIF-8 can effectively prevent premature drug release, thereby minimizing off-target effects and avoiding early release–associated toxicity. To evaluate the loading and release behavior of resveratrol in the ZIF-8 system, the UV absorbance of resveratrol solutions at 306 nm was first measured and found to increase linearly with concentration, allowing construction of a standard calibration curve (Figure S4). Based on these data, the encapsulation efficiency and drug-loading capacity of resveratrol were calculated to be 68.35 ± 1.33% and 40.15 ± 1.58%, respectively, indicating that ZIF-8 serves as a high-capacity drug carrier compared with other delivery systems. We next assessed the in vitro resveratrol release profile from ZIF-8@Res@PEG-FA in PBS at pH values of 5.5, 6.5, and 7.5 over time (Figure A). At pH 5.5, approximately 70.6 ± 2.5% of resveratrol was released within 8 h, significantly higher than at pH 7.4 or pH 6.5, indicating that an acidic inflammatory microenvironment facilitates resveratrol release. This pH-responsive behavior enables ZRF to achieve site-specific drug release and supports its potential for multimodal, targeted therapeutic intervention. Before therapeutic application, the biocompatibility of the nanoparticles was evaluated. Cytotoxicity of ZRF was assessed using the CCK-8 assay in three human cell types (VSMCs, HUVECs, and 293T cells). At 200 μg/mL, cell viability remained above 90% across all three cell lines, indicating negligible cytotoxicity and good biocompatibility (Figure B).

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(A) Cumulative release percentage of RES from ZIF-8@RES@PEG-FA in solutions at different pH values. (B) Cytotoxicity of ZIF-8@RES@PEG-FA at different concentrations in VSMCs, HUVECs, and 293T cells. (C, D) Representative confocal laser-scanning microscopy (CLSM) images of M0 and M1 macrophages incubated with Cy5.5-labeled ZIF-8@RES@PEG-FA or ZIF-8@RES for 4 h at 37 °C; nuclei were counterstained with Hoechst 33342 (blue). Scale bar: 50 μm; magnified scale bar: 10 μm. (E) CLSM images of RAW 264.7 cells after 24 h of treatment with the following groups (Control, LPS, LPS+ZIF-8, LPS+RES, LPS+ZIF-8@RES, and LPS+ZIF-8@RES@PEG-FA) were obtained using DCFH-DA as the ROS fluorescent probe. Scale bar: 100 μm. Data are presented as mean ± SD (n = 3).

3.2.2. Cellular Uptake Assay

To assess the targeting capability of ZIF-8@Res@PEG-FA toward M1 macrophages, we first compared the in vitro internalization efficiencies of Cy5.5-labeled ZIF-8@Res and ZIF-8@Res@PEG-FA in two macrophage phenotypes: M0 (resting) and M1 (LPS-activated). Confocal laser scanning microscopy (CLSM) analysis showed that M1 macrophages incubated with Cy5.5-ZRF exhibited markedly higher Cy5.5 fluorescence than M0 macrophages, indicating significantly higher cellular uptake (Figures C and S5). In contrast, when exposed to Cy5.5-ZIF-8@Res, no significant difference in uptake was observed between M0 and M1 macrophages (Figures D and S5). These results strongly support the conclusion that PEG-FA modification confers enhanced targeting capability to the nanocarrier, particularly toward M1 macrophages. This observation is consistent with previous reports and suggests that the targeting effect is mediated by specific recognition of integrin αvβ3, which is expressed on M1 macrophages and represents a dominant macrophage subtype in aortic dissection.

3.2.3. Reactive Oxygen Species (ROS) Scavenging Assay

Reactive oxygen species (ROS), natural byproducts of oxidative metabolism, can accumulate excessively under oxidative stress, impairing cellular function. In the AD microenvironment, pronounced oxidative stress drives excessive ROS generation. We investigated the antioxidant and anti-inflammatory effects of ZIF-8@Res@PEG-FA in the RAW 264.7 murine macrophage cell line. According to the experimental design, RAW 264.7 cells were stimulated with lipopolysaccharide (LPS) to polarize them toward the pro-inflammatory M1 phenotype. The macrophages were then incubated with the nanoparticles, and no obvious cytotoxicity of the nanocatalytic material was observed (Figure S6). Intracellular ROS levels were measured using 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) as a fluorescent probe. Confocal laser scanning microscopy (CLSM) images showed that, after ZRF treatment, the green fluorescence signal from oxidized DCFH-DA was markedly reduced in M1 macrophages, indicating that the internalized nanoparticles effectively suppressed intracellular ROS generation. These results further confirm the potent antioxidant activity of ZRF (Figures E and S7).

3.3. Cellular Anti-Inflammatory Effect of ZIF-8@Res@PEG-FA

3.3.1. Biomimetic Nanomaterials Promote VSMC Proliferation and HUVEC Angiogenesis

Previous studies have shown that excessive production of reactive oxygen species (ROS), including superoxide anions (O2 –) and hydrogen peroxide (H2O2), occurs in patients with aortic dissection (AD) due to multiple pathological factors. This oxidative stress disrupts vascular smooth muscle cell (VSMC) and endothelial cell (EC) function, impairing endothelial repair at intimal tears. Vascular repair is initiated by endothelial sprouting, followed by degradation of the endothelial basement membrane and subsequent endothelial cell migration and proliferation, which form lumen-containing tubular structures. Benefiting from the sustained release of resveratrol and zinc ions from the ZIF-8@Res@PEG-FA delivery system, the ZRF biomimetic nanoparticles promote VSMC migration and reduce abnormal cell adhesion. The groups remained largely unhealed. In contrast, both the ZIF-8@Res and ZIF-8@Res@PEG-FA groups significantly promoted VSMC migration under LPS-induced inflammatory conditions, resulting in marked wound closure that approached control levels (Figure A). To further mimic angiogenesis in a three-dimensional environment, a Matrigel tube formation assay was conducted (Figure B). HUVECs treated with ZIF-8@Res and ZIF-8@Res@PEG-FA retained the ability to form well-defined tubular and network-like structures under inflammatory conditions, whereas the LPS and LPS + ZIF-8 groups showed minimal tube formation. These findings indicate that ZRF has pro-angiogenic properties, which may be closely associated with the release of zinc ions from the biomimetic nanoparticles. Zinc has been reported to play a critical role in maintaining vascular network formation and hematopoietic development, and our results confirm that sustained zinc ion release from ZRF stimulates angiogenesis, consistent with previous reports. Importantly, PEG-FA modification modulates zinc ion release, thereby avoiding the potential toxicity reported in earlier studies. Resveratrol also exerts complex, dynamic regulatory effects on angiogenesis; it has been reported to alleviate endothelial injury induced by limb ischemia–reperfusion by modulating Keap1/Nrf2 signaling–mediated oxidative stress. Our results further demonstrate the beneficial effects of resveratrol on HUVEC migration and angiogenesis under LPS-induced oxidative and inflammatory stress.

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(A) Representative bright-field images of scratch wounds at 0 and 24 h after treatment with different formulations. Scale bar: 200 μm. (B) Representative bright-field images of tube formation in different treatment groups. Scale bar: 200 μm. (C) Protein expression levels of α-SMA and MMP2 in VSMCs of different treatment groups detected by Western blot. (D) Quantitative analysis of representative Western blot results for α-SMA and MMP2 in VSMCs protein expression in different treated groups. (E) Protein expression levels of iNOS and Arg-1 in VSMCs of different treatment groups detected by Western blot. (F) Quantitative analysis of representative Western blot results for iNOS and Arg-1 in VSMCs protein expression in different treated groups. (G) TEM images of RAW 264.7 cells in different treatment groups; autolysosomes marked with red triangles. Scale bar: 500 nm. Data are presented as mean ± SD (n = 3). ns, no significance. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

3.3.2. Biomimetic Nanomaterials Promote the Contractile Phenotype of VSMCs and the Anti-Inflammatory Effects

VSMCs are the principal functional cells of the vascular media, and their pathological dysregulation is pivotal in AD progression. The contractile phenotype of VSMCs is essential for maintaining aortic wall integrity, whereas phenotypic switching and metabolic abnormalities are key events in thoracic aortic dissection. Reversing this process is therefore an important therapeutic target. We further investigated the effects of ZIF-8@Res@PEG-FA on VSMC phenotypic modulation. RT-qPCR analysis showed that LPS-induced inflammatory oxidative stress significantly reduced the mRNA expression of contractile markers, including myosin heavy chain 11 (MYH11), transforming growth factor-β2 (TGF-β2), and α-smooth muscle actin (α-SMA). Treatment with ZIF-8@Res@PEG-FA markedly restored their expression (Figure S8 and Table S1). Western blot analysis consistently showed that LPS stimulation decreased α-SMA protein expression, whereas the ZIF-8@Res@PEG-FA group exhibited a pronounced increase in α-SMA protein levels compared with the other treatment groups (Figure C,D). Matrix metalloproteinases (MMPs) are key regulators of extracellular matrix (ECM) degradation and play critical roles in cell migration and tissue remodeling in both physiological and pathological contexts. Previous studies have shown that VSMC-secreted MMP-2 contributes significantly to ECM degradation in AD. Western blot analysis showed that LPS-induced inflammatory oxidative stress led to overexpression of MMP-2 in VSMCs, whereas treatment with ZIF-8@Res@PEG-FA markedly reduced MMP-2 expression (Figure C,D). Collectively, these findings indicate that ZIF-8@Res@PEG-FA preserves the contractile phenotype of VSMCs, suppresses ECM degradation, and provides a mechanistic basis for the therapeutic potential of ZRF in treating aortic dissection. To evaluate the anti-inflammatory effects of the biomimetic nanoparticles, protein expression levels of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2), α-smooth muscle actin (α-SMA), and arginase-1 (Arg-1) were assessed by Western blotting. Immunoblotting results showed that LPS stimulation of RAW 264.7 macrophages markedly increased expression of the pro-inflammatory protein iNOS and decreased expression of Arg-1. In contrast, treatment with ZIF-8@Res@PEG-FA reversed these effects (Figure E,F). Given that iNOS is a characteristic marker of M1 macrophages and that Arg-1 is a marker of M2 macrophages, which upregulates anti-inflammatory and tissue-repair–associated genes, these findings indicate that ZRF effectively promotes macrophage polarization from the M1 to the M2 phenotype under inflammatory conditions. In addition, transmission electron microscopy (TEM) images (Figure G) revealed that LPS-stimulated macrophages exhibited a pronounced increase in both the number and size of lysosomes, forming abundant mature lysosomes characteristic of M1-polarized inflammatory macrophages. In contrast, macrophages coincubated with ZIF-8@Res@PEG-FA exhibited fewer, smaller lysosomes, predominantly immature, a feature reported to be associated with M2 polarization. Immunofluorescence staining further confirmed modulation of macrophage polarization.

3.4. Effect of Biomimetic Nanoparticles on Macrophage Polarization

Accumulating evidence indicates that polarization of macrophages toward the pro-inflammatory M1 phenotype plays a critical role in the progression of aortic dissection (AD). Oxidative stress and inflammation reinforce each other, creating a vicious cycle that accelerates disease progression and increases the risk of aortic rupture. LPS-induced M1 macrophages exhibited strong green fluorescence, whereas treatment with ZIF-8@Res@PEG-FA markedly reduced CD80 fluorescence intensity. Conversely, expression of CD206, a representative M2 marker, was significantly increased, indicating that ZRF effectively drives macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype (Figure A,B). Flow cytometric analysis further showed that ZIF-8@Res@PEG-FA downregulated CD80 and upregulated CD206 in macrophages (Figure C,D). Moreover, ZIF-8@Res@PEG-FA treatment suppressed expression of pro-inflammatory genes, including tumor necrosis factor-α (TNF-α) and iNOS (Figure E–G), while upregulating anti-inflammatory and tissue-repair–associated genes, such as interleukin-4 (IL-4) and Arg-1 (Figure H–J). Collectively, these results demonstrate that ZIF-8@Res@PEG-FA biomimetic nanoparticles effectively promote polarization of pro-inflammatory M1 macrophages toward the anti-inflammatory M2 phenotype.

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Modulation of macrophage polarization by ZIF-8@RES@PEG-FA. (A, B) CLSM images showing expression of CD80 and CD206 in RAW 264.7 cells across different treatment groups, with corresponding fluorescent staining; green channel: CD80, red channel: CD206, blue channel: DAPI. Magnified scale bar: 50 μm. (C, D) Expression of CD80 and CD206 in RAW 264.7 cells from different treatment groups detected by flow cytometry. (E) Mean fluorescence intensity (MFI) quantification of CD80 in (A). (F, G) Expression levels of TNF-α and iNOS in RAW 264.7 cells from different treatment groups were measured by RT-PCR. (H) MFI quantification of CD206 in (B). (I, J) Expression levels of IL-4 and Arg-1 in RAW 264.7 cells from different treatment groups were detected by RT-PCR. n = 3 per group, one-way ANOVA with Dunnett’s multiple comparisons test was used. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001; ns, not significant.

3.5. Therapeutic Efficacy of Biomimetic Nanomaterials In Vivo

Aortic dissection (AD) was induced in 3-week-old C57BL/6J mice by administering 0.5% β-aminopropionitrile (BAPN), a specific lysyl oxidase inhibitor, in the drinking water for 4 consecutive weeks. After successful model establishment, mice received intravenous injections of phosphate- buffered saline containing ZIF-8@Res@PEG-FA nanoparticles as a therapeutic intervention, and systemic parameters were monitored throughout the experiment. The results showed that body weight in the ZIF-8@Res@PEG-FA–treated group did not fluctuate significantly (Figure A), whereas the survival rate was markedly improved compared with the control group (Figure B), accompanied by a significant reduction in the incidence of aortic dissection (Figure C). Gross photography and ultrasound imaging revealed pronounced dilation of the aortic arch in the BAPN-only group (Figure D), indicative of aneurysmal expansion, a common precursor or concomitant feature of aortic dissection. In contrast, treatment with ZIF-8@Res@PEG-FA effectively alleviated early aneurysmal dilation and markedly suppressed disease progression, demonstrating robust therapeutic efficacy (Figure S9). To further evaluate pathological changes before and after treatment, multiple histological and immunohistochemical analyses were performed, including hematoxylin and eosin (H&E) staining, elastic van Gieson (EVG) staining, Masson-Bröckers trichrome staining, and immunohistochemical staining for α-smooth muscle actin (α-SMA) and osteopontin. The BAPN-only group exhibited characteristic pathological changes, including intimal tearing, fragmentation and degradation of elastic fibers, abnormal collagen deposition, and phenotypic switching of vascular smooth muscle cells (VSMCs). In contrast, ZIF-8@Res@PEG-FA treatment substantially mitigated these pathological injuries and preserved the structural integrity of the aortic wall (Figures E and S10). Immunofluorescence staining further showed a marked increase in infiltration of CD86+ macrophages (M1 phenotype) and a concomitant reduction in CD206+ macrophages (M2 phenotype) within aortic lesions in the BAPN group (Figure F,G), indicating pronounced local inflammation. Notably, ZIF-8@Res@PEG-FA treatment effectively suppressed the recruitment and infiltration of M1 macrophages while promoting M2 macrophage infiltration and polarization, thereby exerting potent anti-inflammatory effects and attenuating further VSMC damage. Importantly, no significant abnormalities were observed in serum biochemical and hematologic parameters after ZIF-8@Res@PEG-FA treatment (Figures S11, and S12), indicating minimal impact on systemic metabolic function. In addition, all nanoparticle formulations exhibited good hemocompatibility (Figure S13). Histological examination of major organs, including the heart, liver, spleen, lungs, and kidneys, revealed no apparent pathological changes on H&E staining (Figure S14), further confirming the favorable in vivo biosafety profile of ZIF-8@Res@PEG-FA nanoparticles. ZIF-8 gradually degrades under physiological conditions, releasing zinc ions that are efficiently regulated and metabolized by the endogenous zinc homeostasis system in normal organs, thereby preventing zinc overaccumulation and organ toxicity. Together with H&E staining and serum biochemistry results, these findings confirm the nanoplatform’s favorable biocompatibility and in vivo biosafety.

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In vivo therapeutic effects of ZIF-8@RES@PEG-FA. (A, B) Body weight and survival rate of mice in the PBS group, BAPN group, and ZIF-8@RES@PEG-FA (50 mg/kg) intravenous injection group (n = 10). (C) AD formation in mice of different groups. (D) Digital photographs and ultrasound images of aortic tissues in different groups; white and red arrows point to the aortic arch. (E) Changes in aortic tissues of each treatment group were detected by immunohistochemical staining (H&E, EVG, Masson, α-SMA, OPN). Scale bar: 50 μm. (F, G) Expression of CD86 and CD206 in aortic tissues from different groups detected by immunofluorescence staining. Scale bar: 50 μm. Data are presented as mean ± SD.

4. Conclusions

To address current limitations in diagnosing and treating aortic dissection (AD), we developed a biomimetic nanoplatform, ZIF-8@Res@PEG-FA, and, for the first time, proposed a therapeutic strategy that synergistically scavenges reactive oxygen species (ROS) and suppresses inflammation for AD treatment. In vitro experiments demonstrated that ZIF-8@Res@PEG-FA exerts potent antioxidant and anti-inflammatory effects by promoting the polarization of pro-inflammatory M1 macrophages toward the anti-inflammatory M2 phenotype. This anti-inflammatory activity further protects vascular smooth muscle cells (VSMCs) from ROS-induced and inflammation-mediated injury and helps maintain a physiological contractile VSMC phenotype, thereby slowing AD progression. In a β-aminopropionitrile (BAPN)-induced aortic dissection mouse model, ZIF-8@Res@PEG-FA nanoparticles significantly attenuated aortic inflammation and markedly suppressed aortic dilation, effectively inhibiting AD progression. Collectively, these findings indicate that this biomimetic nanoplatform, through combined antioxidative and anti-inflammatory mechanisms, has the potential to restore redox homeostasis and preserve vascular wall cell function, offering broad prospects for treating aortic dissection and other inflammatory vascular diseases.

Supplementary Material

ao6c02956_si_001.pdf (733.6KB, pdf)

Acknowledgments

This work was supported by the Medical Scientific Research Project of Changzhou Health Commission (Grant No. ZD202207). We would like to thank Southeast University for providing the confocal microscopy imaging and animal facility support for the in vivo animal experiments. The graphical abstract and schematic illustrations were created with BioRender.com.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c02956.

  • Materials, characterizations, detailed methods, lower-magnification TEM image, article size characterization, resveratrol calibration curve, quantitative analysis of cellular uptake, intracellular ROS, and gene expression; cytocompatibility evaluation; quantitative histological analysis of aortic tissues; hematological and serum biochemical analyses; hemolysis assay; and RT–qPCR primer sequences (PDF)

†.

H.G. contributed to this work. Methodology, writingoriginal draft, investigation, and formal analysis: H.G., J.W., and Z.L; data curation, visualization, and writingreview and editing: D.D., W.H., and X.W.; resources and funding acquisition: X.Z. and H.G.; supervision and conceptualization: H.G., J.W., X.W., Y.H., and X.Z.

The authors declare no competing financial interest.

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Supplementary Materials

ao6c02956_si_001.pdf (733.6KB, pdf)

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