Novel, engineered fusogenic liposome-based anti-oxidant delivery system improves cerebrovascular health in aging

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), impaired neurovascular coupling (NVC) responses and microvascular rarefaction 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 effective usage in vascular cognitive impairment. Our study aimed to address this challenge by introducing a novel drug delivery system designed to enhance the efficiency of polyphenol delivery, both in vitro and in vivo. 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 more efficiently target CMVECs and enhance liposomal uptake, with the ultimate objective of effectively delivering RSV to the brain's microvascular endothelium in aging subjects (ApoE-FL-RSV). Our investigation focused on characterizing the cellular uptake of ApoE-FL by CMVECs in vitro and analyzing its biodistribution and pharmacokinetics in vivo. ApoE-FL exhibited significantly higher accumulation in CMVECs compared to control FL in vivo. In in vitro studies, ApoE-FL demonstrated a strong affinity for binding to the membrane of CMVECs, and knockdown of low-density receptor-related protein (LRP1 - ApoE receptor) significantly reduced its uptake, confirming an ApoE-dependent docking mechanism. Using advanced in vivo multiphoton imaging, we longitudinally assessed the effects of ApoE-FL-RSV on the BBB. The findings showed a marked rejuvenation of endothelial barrier function, along with restored vascular density in the cortex and hippocampus, as well as enhanced NVC in aged mice treated with ApoE-FL-RSV. In light of these results, we concluded that the ApoE-coated fusogenic liposomal delivery system holds promise as a viable pharmacological solution for addressing age-related vascular cognitive impairment. RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614, R01NS100782, R01CA255840, AHA.24CDA1276505.pc.gr.193648, AHA916225, AHA CDA941290, and PHF. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.