Lipidoid nanoparticles increase ATP uptake into hypoxic brain endothelial cells

Area of Science:

• Biotechnology
• Nanomedicine
• Drug Delivery

Background:

• Lipidoid nanoparticles (LNPs) are established carriers for nucleic acid delivery to liver and muscle.
• The application of LNPs for small molecule drug delivery, particularly to the central nervous system (CNS), remains largely unexplored.
• Brain endothelial cells (BECs) form the blood-brain barrier (BBB) and are critical targets for CNS therapeutics.

Purpose of the Study:

• To investigate the potential of LNPs for delivering small molecule drugs to BECs.
• To evaluate the efficacy of adenosine triphosphate (ATP)-loaded LNPs in enhancing cellular energetics of BECs.
• To characterize the physicochemical properties and stability of ATP-loaded LNPs.

Main Methods:

• Formulation and characterization of ATP-loaded LNPs using C12-200 ionizable cationic lipid and helper lipids, including polyethylene glycol-dimyristoyl glycerol (PEG-DMG).
• Assessment of colloidal stability of LNPs in isolation and in the presence of serum proteins.
• Quantification of ATP uptake into normoxic and hypoxic BECs using ATP-loaded LNPs.

Main Results:

• The inclusion of PEG-DMG was critical for maintaining the colloidal stability of LNPs over time.
• ATP-loaded LNPs demonstrated enhanced colloidal stability in the presence of serum proteins.
• ATP-LNPs significantly increased ATP uptake into both normoxic (7.7-fold) and hypoxic (6.6-fold) BECs.

Conclusions:

• LNPs show promise as a novel delivery system for small molecular mass actives to BECs.
• This study demonstrates the feasibility of using LNPs to deliver ATP to BECs, potentially improving cellular energetics.
• The findings support the development of LNP-based therapies targeting the CNS via the blood-brain barrier.