Synergistic dual cell therapy for atherosclerosis regression: ROS-responsive Bio-liposomes co-loaded with Geniposide and Emodin.
Journal of nanobiotechnology
The development of nanomaterials for delivering natural compounds has emerged as a promising approach for atherosclerosis therapy. However, premature drug release remains a challenge. Here, we present a ROS-responsive biomimetic nanocomplex co-loaded with Geniposide (GP) and Emodin (EM) in nanoliposome particles (LP NPs) for targeted atherosclerosis therapy. The nanocomplex, hybridized with the macrophage membrane (Møm), effectively evades immune system clearance and targets atherosclerotic plaques. A modified thioketal (TK) system responds to ROS-rich plaque regions, triggering controlled drug release. In vitro, the nanocomplex inhibits endothelial cell apoptosis and macrophage lipid accumulation, restores endothelial cell function, and promotes cholesterol effluxion. In vivo, it targets ROS-rich atherosclerotic plaques, reducing plaque area ROS levels and restoring endothelial cell function, consequently promoting cholesterol outflow. Our study demonstrates that ROS-responsive biomimetic nanocomplexes co-delivering GP and EM exert a synergistic effect against endothelial cell apoptosis and lipid deposition in macrophages, offering a promising dual-cell therapy modality for atherosclerosis regression.
10.1186/s12951-024-02389-5
An apoptotic body-biomimic liposome in situ upregulates anti-inflammatory macrophages for stabilization of atherosclerotic plaques.
Wu Yue,Zhang Yong,Dai LiLi,Wang QianQian,Xue LingJing,Su Zhigui,Zhang Can
Journal of controlled release : official journal of the Controlled Release Society
The macrophages mediated inflammation participates in every stage of atherosclerosis. Attenuation of macrophages inflammatory responses by active ingredients in atherosclerotic plaques is benefit to atherosclerotic stabilization and regression, but meanwhile, it is highly desired to develop accurate therapeutics for reducing off-target effects. Previous studies revealed that the apoptotic bodies are effectively recognized and engulfed by macrophages own to increased exposure of phosphatidylserine (PtdSer), which is regarded as a key "eat-me" signal. To achieve optimal delivery efficiency, an apoptotic body biomimic liposome (AP-Lipo) is constructed by decorating PtdSer and DSPE-PEG2000-cRGDfK onto the surface of liposome for selectively delivering pioglitazone (PIO), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, into atherosclerotic macrophages while minimizing its side effects. Compared with unmodified liposome, AP-Lipo is more effective to recognize and penetrate the activated vascular endothelial monolayer, target pro-inflammatory macrophages and suppress the inflammation by upreglation of anti-inflammatory cytokines in vitro. Moreover, AP-Lipo can effectively target to atherosclerotic plaques and imped the progression of atherosclerosis by upregulating anti-inflammatory macrophages number and stabilizing the atherosclerotic plaques. In summary, this design imitates the characteristic of apoptotic body and provides a potential drug delivery system for atherosclerosis and other diseases, which attribute to inflammation mediated by macrophages.
10.1016/j.jconrel.2019.10.043
LPS adsorption and inflammation alleviation by polymyxin B-modified liposomes for atherosclerosis treatment.
Acta pharmaceutica Sinica. B
Chronic inflammation is critical in the onset and progression of atherosclerosis (AS). The lipopolysaccharide (LPS) level in the circulation system is elevated in AS patients and animal models, which is correlated with the severity of AS. Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype, aggravate inflammation, and ultimately contribute to the exacerbation of AS, LPS in the circulation system was supposed to be the therapeutic target for AS treatment. In the present study, polymyxin (PMB) covalently conjugated to PEGylated liposomes (PLPs) were formulated to adsorb LPS through specific interactions between PMB and LPS. , the experiments demonstrated that PLPs could adsorb LPS, reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells. , the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines, decreased the proportion of M1-type macrophages in AS plaque, stabilized AS plaque, and downsized the plaque burdens in arteries, which eventually attenuated the progression of AS. Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.
10.1016/j.apsb.2023.06.005
Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability.
Journal of controlled release : official journal of the Controlled Release Society
Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls. Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been purported to be of therapeutic benefit to atherosclerosis patients. However, large clinical trials have yielded inconsistent data, likely due to variations in the formulation, dosage, and bioavailability of DHA following oral intake. To fully exploit its potential therapeutic effects, we have developed an injectable liposomal DHA formulation intended for intravenous administration as a plaque-targeted nanomedicine. The liposomal formulation protects DHA against chemical degradation and increases its local concentration within atherosclerotic lesions. Mechanistically, DHA liposomes are readily phagocytosed by activated macrophages, exert potent anti-inflammatory and antioxidant effects, and inhibit foam cell formation. Upon intravenous administration, DHA liposomes accumulate preferentially in atherosclerotic lesional macrophages and promote polarization of macrophages towards an anti-inflammatory M2 phenotype, resulting in attenuation of atherosclerosis progression in both ApoE and Ldlr experimental models. Plaque composition analysis demonstrates that liposomal DHA inhibits macrophage infiltration, reduces lipid deposition, and increases collagen content, thus improving the stability of atherosclerotic plaques against rupture. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) further reveals that DHA liposomes can partly restore the complex lipid profile of the plaques to that of early-stage plaques. In conclusion, DHA liposomes offer a promising approach for applying DHA to stabilize atherosclerotic plaques and attenuate atherosclerosis progression, thereby preventing atherosclerosis-related cardiovascular events.
10.1016/j.jconrel.2023.06.035
An elastase-inhibiting, plaque-targeting and neutrophil-hitchhiking liposome against atherosclerosis.
Acta biomaterialia
Neutrophil extracellular traps (NETs) play a crucial role in the formation of vulnerable plaques and the development of atherosclerosis. Alleviating the pathological process of atherosclerosis by efficiently targeting neutrophils and inhibiting the activity of neutrophil elastase to inhibit NETs is relatively unexplored and is considered a novel therapeutic strategy with clinical significance. Sivelestat (SVT) is a second-generation competitive inhibitor of neutrophil elastase with high specificity. However, therapeutic effect of SVT on atherosclerosis is restricted because of the poor half-life and the lack of specific targeting. In this study, we construct a plaque-targeting and neutrophil-hitchhiking liposome (cRGD-SVT-Lipo) to improve the efficacy of SVT in vivo by modifying the cRGD peptide onto SVT loaded liposome, which was based on the interaction between cRGD peptide and integrin ανβ3 on the surface of cells in blood and plaque, including epithelial cell, macrophage and neutrophils. The cRGD-SVT-Lipo could actively tend to or hitchhike neutrophils in situ to reach atherosclerotic plaque, which resulted in enhanced atherosclerotic plaque delivery. The cRGD-SVT-Lipo could also reduce plaque area, stabilize plaque, and ultimately alleviate atherosclerosis progression through efficiently inhibiting the activity of neutrophil elastase in atherosclerotic plaque. Therefore, this study provides a basis and targeting strategy for the treatment of neutrophil-related diseases. STATEMENT OF SIGNIFICANCE: Neutrophil extracellular traps (NETs)-inhibiting is a prospective therapeutic approach for atherosclerosis but has received little attention. The NETs can be inhibited by elastase-restraining. In this work, an intriguing system that delivers Sivelestat (SVT), a predominantly used neutrophil elastase inhibitor with poor targeting capability, is designed to provide the drug with plaque-targeting and neutrophil-hitchhiking capability. The result suggests that this system can effectively hinder the formation of NETs and delay the progression of atherosclerosis.
10.1016/j.actbio.2023.11.020
ROS Responsive Nanoplatform with Two-Photon AIE Imaging for Atherosclerosis Diagnosis and "Two-Pronged" Therapy.
Ma Boxuan,Xu Hong,Zhuang Weihua,Wang Yanan,Li Gaocan,Wang Yunbing
Small (Weinheim an der Bergstrasse, Germany)
Atherosclerosis, characterized by endothelial injury, progressive inflammation, and lipid deposition, can cause cardiovascular diseases. Although conventional anti-inflammatory drugs reveal a certain amount of therapeutic effect, more reasonable design on plaque targeting, local anti-inflammation, and lipid removal are still required for comprehensive atherosclerosis therapy. In this work, a theranostic nanoplatform is developed for atherosclerosis recognition and inhibition. A two-photon aggregation-induced emission (AIE) active fluorophore (TP) developed is linked to β-cyclodextrin (CD) with a ROS responsive bond, which can carry prednisolone (Pred) in its entocoele via supramolecular interaction to build a diagnosis-therapy compound two-photon fluorophore-cyclodextrin/prednisolone complexes (TPCDP). With TPCDP packaged by nanosized micelles based on a ROS sensitive copolymer poly (2-methylthio ethanol methacrylate)-poly (2-methacryloyloxyethyl phosphorylcholine), the TPCDP@PMM can accumulate in atherosclerotic tissue through the damaged vascular endothelium. Activated by the local overexpressed ROS and rich lipid, the micelles are interrupted and TPCDP is further disintegrated with Pred release due to the relatively stronger interaction of lipid with CD, resulting in anti-inflammatory activity and lipid removal for atherosclerosis inhibition. Besides, labeled with the TP, TPCDP@PMM indicates a distinct two-photon AIE imaging on atherosclerosis recognition. The "two-pronged" therapeutic effect and plaque location ability has been confirmed in vivo on ApoE mice, holding TPCDP@PMM a great promise for atherosclerosis theranostics.
10.1002/smll.202003253