Apolipoprotein E Mimetics in Targeted Drug Delivery: Advances and Therapeutic Potential for Neurodegenerative and...

The need to improve the delivery of therapeutic compounds that require effective intracranial delivery across the Blood-Brain Barrier (BBB) has generated significant interest in apolipoprotein E (ApoE) mimetic peptides. These synthetic equivalents of the lipid-binding receptorsinteracting domains of natural ApoE are frequently reproducible when incorporated into nanocarriers or nano platforms, including reconstituted low-high density lipoproteins, polymeric nanoparticles, and liposomal systems. The progress in formulation science has led to the development of ApoE- functionalized nanoparticles and multifunctional liposomes with improved BBB translocation, cellular internalization, and Amyloid-beta (Aβ) affinity compared to conventional delivery vehicles. This review provides a comprehensive discussion of the process by which ApoE mimetics can be used to deliver therapeutic drugs and evaluates the different nanocarrier designs adapted to deliver drugs into the nervous system. Emphasis is also placed on new multifunctional systems in which ApoE mimetics are conjugated to therapeutic or diagnostic molecules, enabling imaging of the targeted area, delivery to the disease site, and disease-specific activity. Although the right direction has been taken, several issues still need to be addressed before ApoE-based strategies can be implemented in clinical practice. The problems that continue to limit larger use include formulation stability, unintended off-target interactions, pharmacokinetics, and scalability of complex nanocarrier systems. This review identifies key concerns needed to move ApoE-mimetic technologies toward effective, clinically viable therapies for central nervous system diseases, identifies the issues that inhibit progress, and analyzes possible methods for their management.