Cardiovascular diseases (CVDs) remain the primary contributor to global mortality [1]. Atherosclerosis (AS), the most prevalent CVD subtype, is driven by immune-inflammatory maladaptation [2]. Exosome-mediated crosstalk amplifies this pathology by shuttling inflammatory mediators that exacerbate endothelial dysfunction, oxidized lipid retention, and plaque vulnerability to thrombotic rupture [3,4].

Endothelial cells, strategically positioned at the blood-vessel interface, orchestrate immune-inflammatory responses through interactions with circulating mediators. Oxidized low-density lipoprotein (ox-LDL) triggers endothelial inflammation, while simultaneously recruiting monocytes that differentiate into lipid-laden macrophages [5,6]. This immune-metabolic injury disrupts endothelial barrier integrity, enabling ox-LDL infiltration and perpetuating oxidative stress-induced damage [7,8]. The resulting immune-inflammatory feedback loop accelerates plaque necrotic core expansion. Therapeutic targeting of this endothelial-immune axis offers precision strategies to decouple inflammation from atherogenesis.

ATP-binding cassette transporter A1 (ABCA1), a key regulator of endothelial immunometabolic homeostasis, plays a critical role in regulating cellular cholesterol efflux and initiating the biogenesis of high-density lipoprotein (HDL) particles [9]. This transporter facilitates the transfer of free cholesterol and phospholipids to apolipoprotein A-I, forming nascent HDL precursors that mature through lecithin-cholesterol acyltransferase-mediated esterification. The ABCA1-dependent pathway is indispensable for maintaining vascular homeostasis, as impaired cholesterol efflux contributes to endothelial dysfunction and accelerates atherogenesis [10].

Matrix metalloproteinases (MMPs), belonging to the metzincin superfamily of zinc-dependent endopeptidases, are pivotal mediators of inflammatory responses through their proteolytic regulation of extracellular matrix (ECM) remodeling and immune cell dynamics [11]. Gelatinases A (MMP2) and B (MMP9) are critically implicated in inflammatory cascades [12]. These enzymes facilitate leukocyte migration by degrading structural components of the basement membrane, particularly type IV collagen, thereby compromising tissue barriers [[13], [14], [15]]. Beyond ECM disruption, both enzymes proteolytically activate latent cytokines and chemokines, perpetuating inflammatory microenvironments. Their overexpression is strongly linked to atherosclerotic plaque destabilization, underscoring their dual roles as effectors and amplifiers of immune-inflammatory pathology.

The tissue inhibitor of metalloproteinase 2 (TIMP2) serves as a pivotal regulator of MMP activity through stoichiometric complex formation [16]. TIMP2 inhibits MMP proteolysis and modulates zymogen activation of MMP2 via interactions with membrane-type MMPs. TIMP2 dysregulation disrupts the MMP/TIMP equilibrium within atherosclerotic plaques, leading to insufficient collagen deposition, thinning of the fibrous cap, and increased susceptibility to rupture [17]. Such imbalances in protease/antiprotease dynamics significantly increase the risks of acute cardiovascular events, including myocardial infarction and ischemic stroke. Moreover, TIMP2 demonstrates dual functionality: beyond suppressing MMP-driven ECM degradation, it regulates immune cell responses through integrin-mediated signaling pathways, thereby influencing both plaque stability and inflammatory cascades. This multifactorial role positions TIMP2 as both a therapeutic agent and a biomarker for assessing cardiovascular risk.

Exosomes, a subset of extracellular vesicles (EVs) with diameters spanning 30–160 nm, are emerging as master orchestrators of atherosclerotic plaque pathobiology, dynamically regulating immune-inflammatory circuits, vascular remodeling, and lipid metabolism through cell-specific cargo transfer [18]. Their molecular payload is selectively packaged, reflecting the pathophysiological state of parent cells, and emerging evidence underscores their dual role in both propagating and resolving atherosclerotic inflammation [4]. Exosomal microRNAs (miRNAs) modulate gene expression by targeting >60 % of protein-coding genes, often through posttranscriptional repression or mRNA degradation [19]. Emerging research has highlighted the diagnostic and therapeutic potential of exosomal biomarkers in AS. Their presence in biofluids offers a non-invasive window into plaque vulnerability and disease progression. Furthermore, engineered exosomes capable of delivering therapeutic miRNAs or anti-inflammatory agents represent a promising strategy to mitigate AS progression by targeting specific molecular pathways.

Although a standardized therapeutic approach for AS remains to be established despite decades of investigation, sonodynamic therapy (SDT) has gained attention as a minimally invasive strategy offering distinct benefits such as enhanced tissue penetration depth, localized targeting precision, and reduced energy dissipation [20]. Previous preclinical investigations revealed that non-lethal SDT (NL-SDT) effectively modulated macrophage phenotypic switching within advanced atheromatous lesions, demonstrating selective therapeutic action [21]. Clinically, a phase-2 trial involving patients with atherosclerotic peripheral artery disease demonstrated that SDT combined with atorvastatin achieved rapid plaque stabilization within 4 weeks, with sustained therapeutic effects persisting for ≥40 weeks [22]. While conventional SDT research prioritizes direct macrophage modulation, our work repositions NL-SDT as an exosome-engineering technology that generates immunoregulatory exosomes with dual plaque-stabilizing functions. For clarity, “SDT” in this context exclusively denotes the NL-SDT protocol.