Functionalized nanoparticles to deliver nucleic acids to the brain for the treatment of Alzheimer's disease

Abstract

Brain-targeted gene delivery across the blood-brain barrier (BBB) is a significant challenge in the 21st century for the healthcare sector, particularly in developing an effective treatment strategy against Alzheimer's disease (AD). The Internal architecture of the brain capillary endothelium restricts bio-actives entry into the brain. Additionally, therapy with nucleic acids faces challenges like vulnerability to degradation by nucleases and potential immune responses. Functionalized nanocarrier-based gene delivery approaches have resulted in safe and effective platforms. These nanoparticles (NPs) have demonstrated efficacy in protecting nucleic acids from degradation, enhancing transport across the BBB, increasing bioavailability, prolonging circulation time, and regulating gene expression of key proteins involved in AD pathology. We provided a detailed review of several nanocarriers and targeting ligands such as cell-penetrating peptides (CPPs), endogenous proteins, and antibodies. The utilization of functionalized NPs extends beyond a singular system, serving as a versatile platform for customization in related neurodegenerative diseases. Only a few numbers of bioactive regimens can go through the BBB. Thus, exploring functionalized NPs for brain-targeted gene delivery is of utmost necessity. Currently, genes are considered high therapeutic potential molecules for altering any disease-causing gene. Through surface modification, nanoparticulate systems can be tailored to address various diseases by replacing the target-specific molecule on their surface. This review article presents several nanoparticulate delivery systems, such as lipid NPs, polymeric micelles, exosomes, and polymeric NPs, for nucleic acids delivery to the brain and the functionalization strategies explored in AD research.

Keywords: Alzheimer’s disease; blood-brain barrier; cell-penetrating peptides; functionalized nanoparticles; gene delivery; nucleic acids; targeting ligands.

FIGURE 1

Mechanisms of action of commonly used nucleic acids. (A) microRNA (miRNA), (B) Small interfering RNA (siRNA), (C) Antisense oligonucleotide (ASO), and (D) Plasmid DNA (pDNA) used in AD therapy (Created in Biorender.com).

FIGURE 2

Different routes of administration of nanotherapeutics to the CNS for the treatment of Alzheimer’s disease (Created in Biorender.com).

FIGURE 3

Structural depiction of different types of nanoparticles along with functionalization strategies for nucleic acid delivery: (A) Polymeric micelles, (B) Liposomes, (C) Solid lipid nanoparticles (SLNs), (D) Nanostructured lipid carriers (NLCs), (E) Polymeric nanoparticles, and (F) Cubosomes (Created in Biorender.com).

FIGURE 4

Secretion of exosomes and nucleic acid delivery mediated by exosomes. (A) Schematic flow of formation of exosomes inside cells. The invagination of the plasma membrane forms ILV, which matures into MVB. MVB then finally releases exosomes from the plasma membrane. (B) Schematic diagram of exosomes representing their lipid architecture, protein markers, and encapsulated contents. (C) Exosomes are internalized by cells through endocytosis, such as clathrin-mediated endocytosis and micropinocytosis, depending on the nature of the exosomes and cell type. The internalized exosomes then fuse with lysosomes to form endolysosomes, eventually escaping the endolysosomal pathway to release nucleic acids into the cytosol (Created in Biorender.com).