Highlights

  • Researchers magnetically guided senolytic vesicles to the largest artery — the aorta — to clear plaques in mice with cardiovascular disease.
  • The senolytic vesicles were able to decrease the total number of senescent cells — dysfunctional cells that emit inflammatory molecules — in the aorta.

Atherosclerosis is the thickening and hardening of blood vessels from plaque buildup, which leads to elevated blood pressure and can ultimately precipitate heart failure. Current treatments include taking lipid-lowering and/or anti-inflammatory drugs with limited efficacy unless taken early in disease progression. Interestingly, senescent cells that release inflammatory molecules accumulate in atherosclerotic plaques, aggravating blood vessels. However, targeting their removal with standard senolytics like dasatinib, quercetin, and navitoclax has proven difficult, hampering research on the capabilities of senolytics to counteract blood vessel plaque accumulation.

Published in Theranostics, Yuan and colleagues from Fourth Military Medical University in China devised a technique utilizing magnetic navigation to externally guide the senolytic vesicles to remove plaque from the aorta, alleviating atherosclerosis. The researchers showed that the new method reduced gene activity associated with senescence in the aorta, suggesting senescent cell removal. While the intended targets of these senolytic vesicles are senescent cells in the aorta, there was concern that the vesicles would accumulate in the liver and initiate cell death in healthy liver cells to cause liver damage. To avoid this, Yuan and colleagues engineered the vesicles’ senolytic mRNA to prevent liver injury. The findings support that targeting blood vessels with senolytics removes plaques to reverse atherosclerosis and illustrates that using magnetically-guided vesicles may serve to effectively target specific tissues with senolytics.

New Senolytic Vesicle Therapy Alleviates Atherosclerotic Plaques and Eliminates Senescent Cells

Yuan and colleagues engineered cellular vesicles — sacs secreted from cells — so that they contained mRNA that produces a protein — BAX — which causes cell death in non-proliferative cells that emit inflammatory molecules (senescent cells). The researchers also fused these vesicles with magnetic nanoparticles so that they could guide them to target tissues with a magnetic field.

To find whether the magnetically-guided senolytic vesicles effectively remove atherosclerotic plaques, Yuan and colleagues injected them into ApoE-/- mice — a strain highly susceptible to atherosclerosis — fed a high-fat diet to induce artery plaque buildup. By guiding the vesicles with a magnetic field to the aorta, the China-based researchers cut the area of the aortic atherosclerotic plaques in half. These results show that the magnetically guided senolytic vesicles eliminate atherosclerotic plaques to potentially reverse atherosclerosis.

(Zhang et al., 2023 | Theranostics) Magnetically guided senolytic vesicles remove atherosclerotic plaques from the aorta. H) The magnetically guided extracellular vesicles with (EViTX+MF)  and without (EVTX+MF) liver cell-specific mRNA target sequences remove atherosclerotic plaques (red coloration) in the aorta. I) The graph illustrates the significantly reduced aortic plaque area with either type of magnetically guided senolytic vesicle.

Yuan and colleagues sought to confirm that the senolytic vesicles eliminate senescent cells to thereby remove atherosclerotic blood vessel plaques. The researchers measured the gene activity for a senescent cell-associated protein — P21 — in the aorta and found that the senolytic vesicles drastically reduced its gene activation. These data provide evidence that the senolytic vesicles remove blood vessel plaques, in part, by eliminating senescent cells.

(Zhang et al., 2023 | Theranostics) The magnetically guided senolytic vesicles substantially reduce gene activity associated with senescent cells. The two types of senolytic vesicles either with (EViTX+MF) or without (EVTX+MF) liver cell specific target sequences drastically reduce gene activity for the senescent cell associated protein P21.

Injected microscopic vesicles accumulate in the body’s detoxifier, the liver, and an overabundance of these senolytic vesicles may trigger cell death in healthy liver cells. Along those lines, Yuan and colleagues inserted liver cell-specific target sites in the senolytic mRNA — BAX — within the vesicles so that liver cells can degrade the senolytic mRNA. They then tested what effect this alteration to BAX mRNA had on liver damage enzyme markers. As designed, the vesicles with liver cell-specific mRNA target sites showed lower levels of liver enzyme markers for liver injury, showing that these molecular alterations protect against off-target effects.

(Zhang et al., 2023 | Theranostics) Senolytic vesicles with liver cell-specific mRNA target sequences for degradation exhibit lowered liver enzyme markers for liver injury. For aspartate transaminase (AST; Figure H), alanine transaminase (ALT; Figure I), and alkaline phosphatase (ALP; Figure J), the liver cell-specific mRNA target sequences for degradation (EViTX+MF) lowered these liver enzyme markers of liver damage compared to senolytic vesicles without the target sequences (EVTX+MF).

“We demonstrated that the engineered [extracellular vesicle]iTx effectively eliminated senescent cells in plaque regions … significantly attenuating the atherosclerotic burden in the aortas,” say Yuan and colleagues.

Magnetically-Guided Senolytic Vesicle Therapy May Take Some Time

The study provides insight that targeting senescent cells in atherosclerotic plaques within blood vessels alleviates atherosclerosis. Moreover, the new technique that Yuan and colleagues used offers a way to target specific tissues like blood vessels with senolytics.

Standard senolytics like dasatinib, quercetin, and navitoclax suppress proteins like BCL-2 that allow senescent cells to evade cell death. This study, however, used BAX mRNA that stimulates, rather than inhibits, these proteins to induce cell death, offering a new means of initiating the elimination of senescent cells. In this way, the new senolytic technique that Yuan and colleagues used in this study to instigate senescent cell death may prove useful for developing more effective senolytics in the future.

A major limitation to the study was that Yuan and colleagues used cellular vesicles derived from a human kidney cancer cell line — HEK293T cells. Since using vesicles from cancer cells could have unforeseen and potentially dangerous side effects, future research should examine whether vesicles taken from stem cells can be used. Stem cell vesicles may not confer the same risk as vesicles from cancer cells.

The use of magnetic fields to target specific tissues with senolytic therapy may serve as an impactful way to treat age-related diseases like atherosclerosis. It may take some time, though, for humans to reap the benefits of this technology. Along those lines, more research is required to make magnetically guided senolytic vesicle therapy the future of senolytic anti-aging treatments.