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DOI: 10.1039/D5TB01392E (Paper) J. Mater. Chem. B, 2025, Advance Article

BODIPY-based fluorescent probes distinguish the heterogeneity of lipid droplets in carotid and femoral atherosclerotic plaques

Biao Jing† ab, Jinting Ge†a, Chengxin Weng†a, Yuhui Wangf, Yuhan Qiab, Huawei Zhangd, Yuezhang Sune, Jiarong Wanga, Hankui Hua, Jichun Zhaoa, Ding Yuana, Bin Huanga, Wang Wan*c and Tiehao Wang*a
aDivision of Vascular Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. E-mail: tiehao.wang@wchscu.cn
bWest China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
cState Key Laboratory of Medical Proteomics, National Chromatographic R. & A. Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China. E-mail: wanwang@dicp.ac.cn
dDepartment of Radiology and Huaxi MR Research Center (HMRRC), West China Hospital, Sichuan University, Chengdu, 610041, China
eState Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
fThe Second Hospital of Dalian Medical University, Dalian, China

Received 11th June 2025 , Accepted 22nd July 2025

First published on 31st July 2025

Abstract

Atherosclerosis (AS), a complex and long-term disease, is a major contributor to cardiovascular complications and a leading cause of death across the globe. Lipid droplets (LDs) are closely involved in the initiation and development of AS plaques. Therefore, visualization and quantification of the complexity of LDs may assist in understanding the biology of atherosclerotic plaques and assessing lesion stability. In this study, we report lipophilic fluorescent sensors based on a BODIPY scaffold (P1 & P2). These probes exhibited fluorescence responsiveness in oil/water systems and lipid droplet mimics (LDMs), with detection limits as low as 50 μg mL−1. In a cellular milieu, the probes effectively tracked LD accumulation induced by oxidized low-density lipoprotein (ox-LDL) as well as lipid suppression caused by treatment with rosiglitazone. Ex vivo imaging of atherosclerotic plaques in ApoE−/− mice and human tissues further demonstrated that these probes could distinguish pathological characteristics across various vascular regions. Collectively, these results highlight the first application of LD sensors in sensing the distinct lipidic lesions in biopsied atherosclerotic plaques from patients, suggesting an organ-specific pathogenesis.

1. Introduction

Atherosclerosis is a chronic, lipid-driven inflammatory disease and represents the underlying pathology of most cardiovascular diseases, including myocardial infarction, stroke, and peripheral artery disease. Lipids, especially cholesterol, cholesteryl ester and triglycerides, accumulate in the arterial intima and trigger a cascade of cellular responses. A crucial consequence of this process is the formation and accumulation of lipid droplets (LDs), which are intracellular organelles that store neutral lipids and actively contribute to the foam cell formation, inflammatory responses, and plaque progression. Unlike extracellular lipids, LDs reflect dynamic intracellular lipid handling and metabolic stresses, serving as both biomarkers and contributors to atherosclerotic progression. The abundance, size, and spatial distribution of LDs have been linked to plaque vulnerability and may differ across vascular beds.1,2 Therefore, advanced quantitative imaging and analysis techniques for LDs—beyond conventional immunohistochemical staining methods of lipids like Oil Red O or Sudan III—are essential for understanding the biology and the pathogenesis of AS, and may offer insights into differential plaque stability and clinical outcomes.

To visualize and study LDs, researchers have devoted extensive efforts to developing LD-targeted fluorescent probes.3–5 Conventional lipophilic probes, such as Nile Red and BODIPY 493/503, exhibit lipid sensitivity and brightness; however, they suffer from drawbacks, such as low specificity, limited Stokes shifts, and photobleaching. In recent studies, Zhang6–8 and Liu9–11 developed several environment-sensitive fluorescent probes. These probes target LDs and analyse surrounding proteins through proximity labelling. Li et al.12–14 worked on fluorescent imaging of reactive oxygen species (ROS) to study LD-related mechanisms in liver disease. Niu et al.15–17 designed a series of aggregation-induced emission (AIE) probes to detect changes in LDs during the course of diseases. These LD probes respond to factors such as polarity,18–20 viscosity,21–23 or oleic acid,24,25 and further enable ratiometric26,27 or fluorescence lifetime imaging.28,29 In parallel, dual-targeted and multifunctional probes have been engineered to monitor interactions between LDs and other organelles.16,30,31 To date, probes have rarely been used to visualize the differences in LD-rich AS plaques from arteries: for example, the heterogeneity of plaques in carotid and femoral vascular territories. Through fluorescent imaging, we can see differences in the amount and size of LDs in plaques across different vascular regions. These differences affect the long-term clinical outcomes of the plaques. For example, carotid artery plaques have larger LD-rich areas. These large LD-rich areas cause necrotic cores, leading to plaque rupture. In contrast, femoral artery plaques have fewer LDs. They often become calcified and fibrotic, causing long-term narrowing of the blood vessels. Addressing this unmet need, our study presents novel BODIPY-based fluorescent probes tailored for the imaging and differentiation of lipid-rich regions in these clinically relevant plaques.

In this work, we developed a couple of BODIPY probes, P1 and P2, for imaging LDs. The probes were evaluated in buffer conditions, cellular systems, disease model animals and finally in clinical atherosclerosis samples. These probes exhibited selectivity for LDs, enabling the detection of lipid-rich regions at concentrations down to 50 μg mL−1. In clinical samples, these BODIPY probes successfully distinguished the morphologies and heterogeneities in AS plaques via fluorescent imaging. This work is the first to use LD sensors in atherosclerotic plaques in different vascular beds and to differentiate different parts of the plaques via fluorescent imaging. These findings of differences in LDs in different parts of atherosclerotic plaques provide preliminary evidence for further investigation of the differences in LDs in different plaques in the human body.

2. Results and discussion

2.1. Design and photophysical characterization of BODIPY-based LD probes

To selectively target lipid species, the BODIPY scaffold was picked as an ideal candidate due to its natural hydrophobicity and lipophobicity. BODIPY 493/503, for instance, is often applied as an LD tracker to stain LDs.32–34 BODIPY 493/503 endows intensive fluorescence emission as well as outstanding photostability. However, the excitation/emission wavelength of a BODIPY-based LD tracker is located in the green light range (493 nm/503 nm), which overlaps with the autofluorescence of tissues, such as elastin and collagen in artery walls, reducing the resolution of bio-imaging.

To resolve the abovementioned issues, we designed a couple of fluorescent probes based on the BODIPY scaffold (Fig. 1a). First, a 2-thiophenylvinyl group was grafted to the skeleton to extend the π-conjugation system. Next, trifluoromethyl (–CF3) groups were substituted onto the meso-phenyl moiety to improve hydrophobicity (Fig. 1b). The emission wavelengths of P1 and P2 were redshifted to 616 nm and 608 nm, respectively. The calculated Log[thin space (1/6-em)]P (C[thin space (1/6-em)]Log[thin space (1/6-em)]P) values of P1 and P2 were 9.37 and 10.28, respectively, which are much higher than the C[thin space (1/6-em)]Log[thin space (1/6-em)]P of BODIPY 493/503 (5.03), indicating that the modified probes are more suitable for monitoring trace lipid components in cells, tissues and organs.


image file: d5tb01392e-f1.tif
Fig. 1 Basic characterization of BODIPY-based LD probes. (a) BODIPY-based probes were used for in vitro and ex vivo imaging of LDs in model systems, foam cells, mouse tissues, and human samples. (b) Synthetic route of the BODIPY-based LD probes. (c) Normalized absorption (10 μM) and (d) emission (10 μM, λex = 570 nm) spectra of P1 and P2 in DMSO. (e) Fluorescence images of P1 and P2 in dioxane/H2O mixtures under 365 nm UV light.

2.2. Fluorescence responses of BODIPY probes in oil–water mixtures and lipid droplet mimics (LDMs)

We first evaluated how these newly designed P1 and P2 probes respond to the polarity of the environment. The fluorescent emission of P1/P2 were measured in mixed solvents with varying ratios of dioxane and water. With an increasing amount of dioxane, the fluorescence of the probes was dramatically turned on (Fig. 1e). This indicated that P1 and P2 are fluorogenic in non-polar environments rather than in aqueous conditions.

Next, we assessed the selectivity of the P1/P2 probes for detecting lipids in aqueous conditions. The fluorescence of P1/P2 was observed in a soybean oil–water system, and their fluorescence in mixtures of soybean oil and water showed that P1/P2 was fully distributed in the oil phase (Fig. 2a). Then, we evaluated the distribution and fluorescence of P1/P2 in lipid droplet mimics (LDMs). LDMs were constructed by the thin-film hydration method with dimyristoylphosphatidylcholine (DMPC) and trilaurin (1[thin space (1/6-em)]:[thin space (1/6-em)]2, w/w) (Fig. 2b). The fluorescence responses of the P1/P2 probes were assessed in the prepared LDM. According to fluorescence measurement, we found that the emission intensity of the probes was in direct proportion to the concentration of LDMs in the range from 0.05 to 3.0 mg mL−1 (R2 = 0.98) (Fig. 2c). Additionally, these probes exhibited a lower limit of detection (LLOD) of 0.05 mg mL−1. These results showed that P1 and P2 possess lipophilicity and environment-responsive fluorescence, making them qualified to track LDs in complex lipid-rich systems.


image file: d5tb01392e-f2.tif
Fig. 2 LD sensing of BODIPY-based probes in oil-rich systems and lipid droplet mimics (LDMs). (a) Fluorescence images of P1 and P2 in soybean oil/water mixtures with different volume ratios under 365 nm UV light. Fluorescence emission spectra (10 μM, λex = 570 nm) of each probe in soybean oil and water. (b) LDMs were prepared by thin-film hydration using DMPC and trilaurin (1[thin space (1/6-em)]:[thin space (1/6-em)]2, w/w). (c) Fluorescence images of P1 and P2 in LDM of different concentrations (0.05–3 mg mL−1) under 365 nm UV light (10 μM). Emission spectra of the probes (10 μM, λex = 550 nm) were measured in LDMs of different concentrations (0.05–3 mg mL−1). All probes exhibited good linear correlation between fluorescence intensity and LDM concentration (R2 = 0.98) (n = 3).

2.3. Detection of lipid droplets in foam cells by probes P1 and P2

To evaluate the ability of the probes to visualize LDs in cellular milieu, we selected RAW264.7 cells, precursors of foam cells, as model systems to estimate the performance of P1/P2. Biosafety was studied first, and a cell viability assay indicated that the probes displayed subtle toxicity up to 10 μM. Next, RAW264.7 macrophages were treated with oxidized low-density lipoprotein (ox-LDL) at different concentrations (0 to 100 μg mL−1) for 48 h to trigger the formation of lipid droplets and a transformation toward foam cells, and the cells were treated with P1 (5 μM) 30 min before imaging (Fig. 3a). The accumulated LDs in the cells were visualized by confocal fluorescence microscopy, and the fluorescence signal of P1/P2 overlapped with the commercial LD tracker, BODIPY 493/503, demonstrating P1/P2 selective targeting of LDs (Fig. 3b). The intensity of the stained LDs was enhanced with increasing ox-LDL concentration (Fig. 3b–d). These lines of evidence confirmed that P1 and P2 were able to quantitatively recognize cellular LDs. To confirm that P1 and P2 tracked the dynamic changes in LDs, rosiglitazone, a PPARγ agonist known to reduce LD content, was selected to tune the content of LD accumulation. We then treated cells with ox-LDL alone or accompanied by rosiglitazone. A diminished signal for the LDs was observed in fluorescence imaging (Fig. 3e), and the corresponding quantitative analysis also showed suppression of LDs, as monitored by the P1/P2 probes (Pearson's correlation coefficients = 0.80 (P1) and 0.97 (P2) with LD tracker; Fig. 3f–g).
image file: d5tb01392e-f3.tif
Fig. 3 BODIPY-based probes were used to detect LDs in foam cells. (a) BODIPY-based probes were used to detect different levels of lipid accumulation in foam cells. (b) Confocal images of P1 in foam cells revealed ox-LDL (0, 50, and 100 μg mL−1, 48 h) induced LD accumulation. Blue: Hoechst 33342; green: LD tracker (BODIPY 493/503) (5 μM); red: P1 (5 μM). Quantification of (c) LD area and (d) total fluorescence intensity per cell showed a dose-dependent increase with ox-LDL. (e) Rosiglitazone was used to reduce lipid accumulation in foam cells, and probes were used to detect LDs under different conditions. (f) Confocal images of cells treated with or without rosiglitazone. P1 and P2 (5 μM) were co-stained with LD tracker. All probes showed LD-selective fluorescence. Quantification of (g) LD area and (h) total fluorescence intensity per cell in foam cells treated with or without rosiglitazone. Statistical analysis by GraphPad: *p < 0.05, **p < 0.01, ***p < 0.001.

2.4. Ex vivo imaging of lipid-rich plaques in ApoE−/− mouse aortas

We next exemplified the fluorescence imaging function of P1/P2 in artery samples. Apolipoprotein E-deficient mice were adopted as a representative animal model to investigate AS pathology. ApoE−/− mice were fed a high-fat diet (HFD) for 6 weeks to induce the formation of atherosclerotic plaques in the aorta. The aortas of the AS mice were dissected, and sections of the plaque lesion area were stained with Oil red O and H&E to clarify the presence of lipidic atherosclerotic plaques (Fig. 4b and c). Compared to wild-type C57BL/6 mice, the plaque signal was seldom captured. Classic biochemical characterizations of AS biomarkers, including triglycerides (TG), total cholesterol (CHO), high-density lipoprotein (HDL) and low-density lipoprotein (LDL), were undertaken, and no significant difference was observed, indicating that the AS model had been successfully constructed (Fig. 4b). The lipid-enriched area of AS plaque were then stained with P1 and P2. The colocalization of P1/P2 with LD tracker confirmed that these probes were capable of identifying AS lesions in tissue sections (Fig. 4c—right two columns, 4d) (Pearson's correlation coefficient = 0.71 (P1) and 0.72 (P2) with LD tracker). In addition, the quantification of the fluorescence signals from P1 and P2 allowed them to distinguish AS plaque from aorta samples (Fig. 4e).
image file: d5tb01392e-f4.tif
Fig. 4 BODIPY-based LD probes were used to detect lipid-rich atherosclerotic plaques in mouse aortas. (a) Compared to C57 mice, ApoE−/− mice fed a high-fat diet (HFD) for 6 weeks showed significantly altered lipid profiles, (b) including elevated triglycerides (TG) and LDL levels. Oil red O staining of whole aortas showed extensive lipid-rich plaques in the ApoE−/− group. (c) Aortic root sections from C57 and ApoE−/− mice were stained with H&E, Oil red O or co-stained with Hoechst 33342 (blue), LD tracker (BODIPY 493/503, green), and probes P1 and P2 (red). (d) Merged fluorescence images showed clear colocalization of LD tracker and P1 or P2 with LD-rich areas in plaques. Quantification of (e) LD area and (f) fluorescence intensity showed significantly higher LD accumulation in ApoE−/− mice. Statistical analysis by GraphPad: *p < 0.05, **p < 0.01.

2.5. The heterogeneity of LDs in human carotid and femoral atherosclerotic plaques

In moving toward clinical AS diagnosis, we investigated whether these probes could differentiate among subtypes of the disease. To evaluate the applicability of BODIPY-based probes for human atherosclerotic tissues, as well as to explore the heterogeneity of AS lesions across vascular regions, we isolated carotid and femoral plaques to conduct further investigations (Fig. 5a). Histological analysis of carotid plaques (patients 1–3) and femoral plaques (patients 4–6) revealed typical structural features by H&E and Oil red O staining (Fig. 5b).
image file: d5tb01392e-f5.tif
Fig. 5 BODIPY-based probes were used to detect and compare LDs in human carotid and femoral atherosclerotic plaques. (a) A schematic illustration of the workflow: clinical samples of carotid and femoral atherosclerotic plaques were collected and incubated with probes P1 and P2 to evaluate differences in LD characteristics. (b) Representative histological and fluorescence images of carotid plaques (patients 1–3) and femoral plaques (patients 4–6). Tissue sections were stained with H&E and Oil red O, and co-stained with Hoechst 33342 (blue), LD tracker (BODIPY 493/503) (green), and probes P1 and P2 (red). (c) LD size distribution, (d) total LDs area and (e) average LD size showed that carotid plaques contained more abundant and larger LDs than femoral plaques. Visualization was performed using staining with P1 and P2. (f) LD fluorescence intensity was also higher in carotid plaques, indicating greater lipid content. Statistical analysis by GraphPad: *p < 0.05, **p < 0.01, ****p < 0.0001.

Carotid and femoral lesions were then stained with Hoechst 33342, LD tracker, and BODIPY-based P1/P2. Quantitative image analysis indicated significant differences in the characteristics of lipidic regions. Compared to femoral plaques, carotid plaques displayed a markedly larger total lipid area and a more intense fluorescence signal (Fig. 5d and f). Moreover, P2 probes consistently yielded a higher signal in terms of both area and intensity, while P2 showed better differentiation of various lesions. Both the average and maximum LD sizes were greater in carotid plaques according to quantitative analysis from P2 (Fig. 5c and e). These findings suggested that the P2 probe successfully revealed that the carotid lesions embedded more abundant foam cells and larger lipid-rich cores, consistent with their more inflammatory and rupture-prone phenotype.

These lines of evidence from imaging results effectively distinguished the two types of plaque not only by total LD burden but also by droplet size and spatial distribution via the fluorescence signals of P1 and P2. These observations align with known hemodynamic and biological differences between the two vascular regions.35,36 The carotid artery, located proximally and subject to disturbed flow, tends to develop lipid-rich, unstable plaques. In contrast, femoral arteries experience more laminar flow and form plaques with less lipid accumulation and greater fibrosis, suggesting a more stable phenotype. Clinically, this translates to divergent outcomes: carotid plaque rupture is a key driver of cerebrovascular events, with rupture rates of 74% in symptomatic and 32% in asymptomatic cases. Femoral plaque rupture is rare (∼0.015%), and associated events typically result from chronic narrowing rather than acute thrombosis.

In summary, BODIPY-based P1 and P2 enabled effective ex vivo imaging of LDs in a cellular environment. In particular, probe P2 was applied to reveal differences in LD abundance, size, and distribution between carotid and femoral artery clinical samples. These differences reflect distinct pathological mechanisms and provide insights into plaque stability and associated clinical risks. The superior sensitivity of P2 further highlights its potential for detailed lipid mapping in tissue-based atherosclerosis studies.

3. Conclusions

In this work, we developed and evaluated BODIPY-based fluorescent probes (P1 and P2) for the selective imaging of lipid droplets (LDs) across cells and atherosclerotic tissues. Structural modifications enhanced their lipophilicity, redshifted emission, and environmental sensitivity, especially in P2. The probes showed excellent performance in model systems and foam cells, enabling real-time tracking of LD dynamics. Ex vivo imaging further revealed distinct LD features in ApoE−/− mouse plaques and in human carotid versus femoral plaques, with P2 providing the highest contrast. These findings demonstrate the potential of BODIPY probes, particularly P2, for LD visualization and plaque characterization, offering insights into lipid metabolism and plaque instability.

Ethics declarations

This study was approved by the Ethics Committee of Animal Experiments of the West China Hospital of Sichuan University for Animal Care and Use (Approval number: 20250218020). Clinical studies were approved by the Ethics Review Committee of the West China Hospital of Sichuan University (No. 2021-1753).

Author contributions

Wang wan: conceptualization, writing – review & editing. Tiehao Wang: conceptualization, project administration. Biao Jing: investigation, visualization, writing – original draft. Jinting Ge: validation, project administration, funding acquisition. Chengxin Weng: validation, resources, funding acquisition. Yuhui Wang: investigation. Yuhan Qi: data curation. Huawei Zhang: visualization, validation. Yuezhang Sun: resources. Jiarong Wang: funding acquisition. Hankui Hu: funding acquisition. Jichun Zhao: supervision. Ding Yuan: supervision. Bin Huang: supervision.

Conflicts of interest

There are no conflicts to declare.

Data availability

All data supporting the findings of this study are available within the article and its SI. No additional datasets were generated or analyzed during the current study.

Fig. (S1–S9), and experimental methods expression and purification of protein, cell culture, confocal fluorescence imaging, etc. See DOI: https://doi.org/10.1039/d5tb01392e

Acknowledgements

This study was granted by the National Natural Science Foundation of China (82470501, 82300542, 82302152), Sichuan Science and Technology Program (2024YFFK003, 2024YFFK0237, 2024YFFK0238, 2024YFFK0239, 2023NSFSC0589), 1⋯3⋯5 project for disciplines of excellence–Clinical Research Fund, West China Hospital, Sichuan University (24HXFH040) and Post-Doctor Research Project of West China Hospital, Sichuan University (2023HXBH108). The funding bodies played no role in the design of the study, the collection, analysis, and interpretation of the data, and the writing of the manuscript. The authors would like to thank Xuanzhi Zhu MD, DDS (State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China) for his assistance in the animal experiments of this manuscript.

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Footnote

† Biao Jing, Jinting Ge and Chengxin Weng contributed equally to the article.
This journal is © The Royal Society of Chemistry 2025
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