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Engineered bifunctional extracellular vesicles simultaneously promoting senolysis and efferocytosis for anti-aging
Mi Qu1, Yang Liu2, Guodong Yang3
1Department of Biochemistry and Molecular Biology, School of Basic Medicine, The Fourth Military Medical University, Xi'an, 710032, China; Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
Abstract:
Cellular senescence underlies age-related dysfunction in diseases such as diabetes, but strategies to concurrently induce senescent cell death and facilitate their clearance remain limited. We here engineered extracellular vesicles (EVs) to load dasatinib and quercetin (D + Q) for senolysis and display avidin on their surface, allowing conjugation with biotinylated anti-VCAM1 for targeting and biotinylated Phosphatidylserine (PS) to promote efferocytosis. The dual-functional EVs were characterized in vitro and validated in diabetic mouse models. The engineered EVs selectively bound senescent cells with high affinity, triggering D + Q-dependent apoptosis. The biotinylated PS modification enhanced macrophage phagocytosis of senescent cells by activating phosphatidylserine-recognition receptor signaling, thereby overcoming senescence-associated efferocytosis inhibition. In diabetic mice, the engineered EVs reduced systemic senescent cell burden and suppressed SASP factors. This resulted in reversed aging phenotypes, including restored renal function and reduced osteoporosis in diabetes. In summary, the engineered EVs combining senolysis and efferocytosis promotion efficiently reverse aging phenotypes in diabetic mice, offering a translational strategy for senescence-related disorders.
Insights
Engineered extracellular vesicles deliver senolytic drugs and promote clearance of senescent cells, reversing aging phenotypes in diabetic mice. This strategy targets cellular senescence and enhances macrophage efferocytosis for treating age-related disorders.
Area of Science:
- Gerontology
- Biotechnology
- Cell Biology
Background:
- Cellular senescence contributes to age-related diseases like diabetes.
- Current strategies for senescent cell elimination are limited.
- Targeting senescent cells offers a therapeutic approach for aging disorders.
Purpose of the Study:
- To engineer extracellular vesicles (EVs) for simultaneous senolysis and enhanced efferocytosis.
- To develop a targeted delivery system for senolytic drugs (dasatinib and quercetin).
- To validate the efficacy of engineered EVs in diabetic mouse models.
Main Methods:
- Engineering EVs to co-load dasatinib and quercetin (D+Q) and display avidin for targeting.
- Conjugating EVs with biotinylated anti-VCAM1 for senescent cell targeting and biotinylated phosphatidylserine (PS) to promote efferocytosis.
- In vitro characterization and in vivo validation in diabetic mouse models.
Main Results:
- Engineered EVs selectively targeted and induced apoptosis in senescent cells via D+Q.
- Biotinylated PS enhanced macrophage phagocytosis of senescent cells, overcoming efferocytosis inhibition.
- In diabetic mice, EVs reduced senescent cell burden, suppressed SASP factors, and reversed aging phenotypes.
Conclusions:
- Engineered EVs effectively combine senolysis and efferocytosis promotion.
- This dual-functional EV strategy reverses aging phenotypes in diabetic mice.
- The approach offers a translational strategy for senescence-related disorders.
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