Delivering Senolytic Nanoparticles to Atherosclerotic Plaques in Mice

Cells become senescent in response to stress and damage, and there is a great deal of stress and damage taking place in the toxic environment of an atherosclerotic plaque. These fatty plaques develop with age in blood vessel walls throughout the body. Many contributing factors determine the age of onset and pace of progression of atherosclerosis, but at the center of it all, atherosclerotic plaques form and grow because macrophage cells of the innate immune system fail to keep up with clearance of excess cholesterol delivered from the bloodstream into blood vessel walls. After a plaque becomes established, it contains toxic altered forms of cholesterol, stressed and dying cells, and certainly a fair number of senescent cells.

Senescent cells are actively harmful to surrounding tissue via the secretion of pro-inflammatory factors. Researchers have in the past shown that removing senescent cells via senolytic treatments can improve the pathology of atherosclerosis in mice, and that cellular senescence is pronounced in cell populations surrounding and involved in an atherosclerotic plaque, such as smooth muscle and endothelium. In today's open access paper, researchers report on a novel way to use nanoparticles to deliver a senolytic payload to atherosclerotic plaques in mice. They employ magnetic guidance as a strategy for localization of nanoparticles via the bloodstream to areas such as the vasculature close to the heart. Unlike some localized senolytic treatments, this does appear beneficial, suggesting the influence of local senescent cells is dominant over the influence of distant senescent cells - at least in this disease and this model. The story might be different in older mice with a greater prevalence of senescent cells throughout the body.

Targeted elimination of senescent cells by engineered extracellular vesicles attenuates atherosclerosis in ApoE-/- mice with minimal side effects

Atherosclerosis (AS) is a prevalent vascular disease characterized by dyslipidemia and chronic inflammation. Despite the use of preventive lipid-lowering and anti-inflammatory therapeutic strategies, there is still a critical need for more effective treatment options. Recent research has revealed a significant accumulation of senescent cells in plaques positively correlated with plaque instability. Senescent cells in plaques aggravate chronic inflammation and accelerate AS progression generating a senescence-associated secretory phenotype (SASP) consisting of matrix remodeling proteases, chemokines, cytokines, growth factors, and lipids. Therefore, the targeted removal of senescent cells in plaques presents a promising therapeutic strategy for treating AS.

BCL-2 associated X protein (BAX), a natural inhibitor of the pro-survival protein, is a key pro-apoptotic protein and plays an essential role in regulating the mitochondrial apoptotic pathway. Increasing the intracellular active BAX level may trigger apoptosis in broad-spectrum senescent cells regardless of origin. Therefore, delivering Bax messenger RNA (mRNA) and the BAX activator BTSA1 to senescent cells may represent a novel approach for clearing senescent cells ("activate the activator").

Superparamagnetic iron oxide nanoparticles (SMN) have recently gained significant attention for targeted drug delivery due to their advanced targeting capacity, biodegradability, biological compatibility, and low toxicity. The ability for magnetic targeting is not dependent on cell types but on the recognition of the spatial location of the affected tissue, rendering it a suitable method for delivering drugs to senescent cells in plaques. Furthermore, small extracellular vesicles (EVs) with a diameter ranging from 30 to 150 nm exhibit favorable biocompatibility and cycling stability, and are well-suited for carrying protein and nucleic acid-based drugs. Thus, Bax mRNA-loaded EVs modified with SMN (EVSMN) hold significant potential as drug carriers for treating AS.

Even for targeted delivery, nanoparticles, including EVs, are accumulated in the liver, causing liver injury when Bax mRNA is excessively delivered. Therefore, repressing Bax translation in liver cells is imperative to avoid potential toxicity. MicroRNAs are key regulators of gene expression that destabilize target mRNAs or inhibit their translation. miR-122-5p (miR-122), is a liver-specific molecule with an estimated cellular abundance of 50,000-82,000 copies in adult liver cells, suggesting that Bax mRNA harboring miR-122 recognition sites in the 3'-untranslated region (3'-UTR) (termed as iBax) could be translationally repressed in liver cells.

Herein, a therapeutic EV (EViTx) was engineered with SMN conjugated on the surface, iBax mRNA encapsulated inside and BAX activator BTSA1 incorporated into the membrane. With external magnetic field (MF) navigation, EViTx, when targeted to atherosclerotic plaques, induced significant apoptosis in senescent cells regardless of origin. Notably, when delivered into liver cells, iBax mRNA was translationally repressed by miR-122 endogenously expressed in liver cells and thus had minimal hepatotoxicity. Repeated delivery of EViTx via tail vein injection achieved high therapeutic efficacy and low side effects in ApoE-/- mice. Hence, the EViTx-based strategy offers a promising treatment approach for AS and other age-related diseases.


would repair's strategy also remove these senescent cells?

Posted by: erasmus at October 12th, 2023 3:34 PM

My understanding is that Repair helps marcrophages ( via RNA as of late ) to tolerate higher levels of SASP, therefore perform their normal RCT. For me this seems like a more root cause than the above article. Once the 7-keto-cholesterol is removed from the lesion, the lesion still has to heal, so the senescent cells there might be useful for that.

Posted by: benoƮt ( paris, france ) at November 4th, 2023 3:43 PM
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