Novel, engineered fusogenic liposome-based anti-oxidant delivery system improves the blood-brain barrier integrity in aging

Abstract

Vascular dysfunction plays a pivotal role in age-related cognitive decline and neurodegeneration. The aging process often leads to a loss of integrity in the blood-brain barrier (BBB), initiating neuroinflammation and contributing to a decline in cognitive function. In previous research, we demonstrated the potential of resveratrol (RSV), a natural polyphenol, to target cerebromicrovascular endothelial cells (CMVECs), effectively countering age-related oxidative stress and improving vascular function, both in vitro and in vivo. However, the limited bioavailability of resveratrol raised questions about its effectiveness concerning the BBB and neuroinflammation. Our study aimed to address this challenge by introducing a novel drug delivery system designed to enhance the effciency of polyphenol delivery. This innovative approach involved the use of fusogenic liposomes (FL) integrated with a bioengineered protein corona (PC) featuring specific apolipoprotein E (ApoE). Our central hypothesis posited that PC formation could be harnessed to directly target CMVECs and enhance liposomal uptake, with the ultimate objective of effectively delivering RSV to the brain's microvessels in aging subjects (ApoE-FL-RSV). Our investigation encompassed the characterization of ApoE-FL uptake by CMVECs, along with an analysis of its biodistribution and pharmacokinetics in vivo. Remarkably, our findings revealed a significant increase in ApoE-FL-RSV accumulation within CMVECs in vivo, compared to control FL uptake. We employed advanced in vivo multiphoton imaging to longitudinally monitor the effects of ApoE-FL-RSV on the BBB, which demonstrated a significant rejuvenation of the endothelial barrier function in aged mice treated with ApoE-FL-RSV. In light of these results, we concluded that the fusogenic liposomal delivery system holds promise as a viable pharmacological intervention for addressing age-related vascular cognitive impairment. AHA834339, RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614, R01NS100782, R01CA255840, and Presbyterian Health Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.