Journal Article

DZNE-2025-00554

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Nanocarrier Drug Release and Blood-Brain Barrier Penetration at Post-Stroke Microthrombi Monitored by Real-Time Förster Resonance Energy Transfer.

Khalin, I. ; Adarsh, N. ; Schifferer, M.DZNE* ; Wehn, A. ; Boide-Trujillo, V. J. ; Mamrak, U. ; Shrouder, J. ; Misgeld, T.DZNE* ; Filser, S. (Last author)DZNE* ; Klymchenko, A. S. ; Plesnila, N.

2025
Soc. Washington, DC

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Please use a persistent id in citations: doi:10.1021/acsnano.4c17011

Abstract: Nanotechnology holds great promise for improving the delivery of therapeutics to the brain. However, current approaches often operate at the organ or tissue level and are limited by the lack of tools to dynamically monitor cargo delivery in vivo. We have developed highly fluorescent lipid nanodroplets (LNDs) that enable tracking of nanocarrier behavior at the subcellular level while also carrying a Förster resonance energy transfer (FRET)-based drug delivery detection system (FedEcs) capable of monitoring cargo release in vivo. Using two-photon microscopy, we demonstrate that circulating LNDs in naïve mouse brain vasculature exhibit 3D real-time FRET changes, showing size-dependent stability over 2 h in blood circulation. Further, in the Nanostroke model, dynamic intravital two-photon imaging revealed that LNDs accumulated within cerebral postischemic microthrombi, where they released their cargo significantly faster than in normal blood circulation. Furthermore, the blood-brain barrier (BBB) became permeable at the microclot sites thereby allowing accumulated FedEcs-LNDs to cross the BBB and deliver their cargo to the brain parenchyma. This microthrombi-associated translocation was confirmed at the ultrastructural level via volume-correlative light-electron microscopy. Consequently, FedEcs represents an advanced tool to quantitatively study the biodistribution and cargo release of nanocarriers at high resolution in real-time. By enabling us to resolve passive targeting mechanisms poststroke, specifically, accumulation, degradation, and extravasation via poststroke microthrombi, this system could significantly enhance the translational validation of nanocarriers for future treatments of brain diseases.

Keyword(s): Blood-Brain Barrier: metabolism (MeSH) ; Blood-Brain Barrier: drug effects (MeSH) ; Animals (MeSH) ; Fluorescence Resonance Energy Transfer (MeSH) ; Mice (MeSH) ; Drug Carriers: chemistry (MeSH) ; Stroke: drug therapy (MeSH) ; Stroke: metabolism (MeSH) ; Drug Liberation (MeSH) ; Nanoparticles: chemistry (MeSH) ; Lipids: chemistry (MeSH) ; Thrombosis: drug therapy (MeSH) ; Thrombosis: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; blood-brain barrier ; correlative light-electron microscopy ; microthrombosis ; nanocarriers ; stroke ; Drug Carriers ; Lipids

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Contributing Institute(s):

1. Neuronal Cell Biology (AG Misgeld)
2. Light Microscopy Facility (CRFS-LMF) (LMF)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 899 - ohne Topic (POF4-899) (POF4-899)

Experiment(s):

1. Light Microscope Facility (CRFS-LMF) / Bonn

Appears in the scientific report 2025

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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