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Gelated Apoptotic Extracellular Vesicles via Enzyme-Instructed Self-Assembly with Multifunctional Microcapsule for Targeted Atherosclerosis Therapy

ABSTRACT: While current atherosclerosis therapies control lipid levels, they poorly regulate macrophages, key drivers of plaque progression. Apoptotic extracellular vesicles (apoEVs) offer a cell-free approach to modulate macrophage-driven inflammation, but their applications are limited by cargo leakage, structural instability, and off-target effects. Herein, we developed engineered apoEVs by combining enzyme-instructed self-assembly (EISA) and surface modification techniques. The hydrogel core formed within apoEVs via EISA enabled efficient encapsulation of atorvastatin while also improving vesicle stability. Concurrently, ROS/pH-responsive degradable microcapsules decorated on the apoEV surface enhanced plaque accumulation through hitchhiking and active targeting via the hyaluronic acid-CD44 interaction. Our engineered apoEVs demonstrated potent anti-atherosclerosis effects both in vitro and in vivo by inhibiting foam cell formation, inducing macrophage repolarization, restoring mitochondrial functions, and improving fibrous cap stability. These therapeutic outcomes were further validated using single-cell transcriptomics and multiplex imaging. This study presents a universal and nondestructive strategy for apoEV engineering and highlights its potential for atherosclerosis therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE343400 | GEO | 2026/08/12

REPOSITORIES: GEO

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Project description:Senescent foamy macrophages are the key pathogenic drivers of atherosclerosis (AS) progression and plaque stability. The RNA N6-methyladenosine (m6A) modification plays an important role in the development of various diseases. However, its role in foamy macrophage aging during AS is still not clarified. To assess m6A methylation levels and m6A modifying enzyme profiles, the infiltrated macrophages were sorted using CD68+ magnetic beads from plaque tissues of patients with AS and high-fat diet feeding Apoe-/- mice. The ALKBH5f/f, Lyz2Cre, Apoe-/- mice were constructed to observe senescent macrophage infiltrated in plaques and AS progression. The RNA-seq, MeRIP, RIP and dual luciferase assays were performed to explore the mechanisms of ALKBH5-mediated formation of senescent macrophage. Downregulated m6A methylation levels and upregulated ALKBH5 expression were observed in aortic plaques and infiltrated macrophages from AS patients and mice. Compared with control mice, ALKBH5f/f, Lyz2Cre, Apoe-/- mice decreased AS plaques and enhanced plaque stability by suppressing senescence of foamy macrophages and senescence-associated secretory phenotypes. In addition, the data of the RNA-seq, MeRIP, RIP and dual luciferase assays showed that ALKBH5 deletion reduced the mRNA level of CC chemokine ligand 5 (CCL5) by increased m6A methylation in macrophages. Actinomycin D assay indicated ALBH5 knockout destroyed stability of Ccl5 mRNA. Mechanismly, ALKBH5 promotes senescent macrophage formation by CCL5/CC chemokine receptor 5 (CCR5)/mTORC1/autophagy signaling. And ALKBH5 induced macrophage derived CCL5 recruits increasingly CD8+IFNγ+ T cells by CCL5-CCR5 axis. Furthermore, the application of ALKBH5 inhibitor IOX-1 and CCR5 monoclonal antibody Adaptavir are potential clinical interventions for the inhibition of senescent macrophage formation and AS progress. Myeloid ALKBH5 deletion mitigates AS progression by suppressing the formation of senescent macrophages and the recruitment of CD8+IFNγ+ T cells. These findings favour the ALKBH5/CCL5/CCR5 signaling as novel targets for atherosclerosis therapy.

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	GSE343400_RAW.tar	Raw
	GSE343400_Sample_1.tar.gz	Other
	GSE343400_Sample_2.tar.gz	Other
	GSE343400_Sample_3.tar.gz	Other

Dataset Information

Gelated Apoptotic Extracellular Vesicles via Enzyme-Instructed Self-Assembly with Multifunctional Microcapsule for Targeted Atherosclerosis Therapy

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