Directing the Way-Receptor and Chemical Targeting Strategies for Nucleic Acid Delivery

Abstract

Nucleic acid therapeutics have shown great potential for the treatment of numerous diseases, such as genetic disorders, cancer and infections. Moreover, they have been successfully used as vaccines during the COVID-19 pandemic. In order to unfold full therapeutical potential, these nano agents have to overcome several barriers. Therefore, directed transport to specific tissues and cell types remains a central challenge to receive carrier systems with enhanced efficiency and desired biodistribution profiles. Active targeting strategies include receptor-targeting, mediating cellular uptake based on ligand-receptor interactions, and chemical targeting, enabling cell-specific delivery as a consequence of chemically and structurally modified carriers. With a focus on synthetic delivery systems including polyplexes, lipid-based systems such as lipoplexes and lipid nanoparticles, and direct conjugates optimized for various types of nucleic acids (DNA, mRNA, siRNA, miRNA, oligonucleotides), we highlight recent achievements, exemplified by several nucleic acid drugs on the market, and discuss challenges for targeted delivery to different organs such as brain, eye, liver, lung, spleen and muscle in vivo.

Keywords: lipoplex; pDNA; polyplex; siRNA; targeting.

Fig. 1

Nonviral carriers for the delivery of different nucleic acids, including their main components, particle types as well as shielding and targeting agents for organ- or cell-specific delivery upon systemic injection. Created with BioRender.com

Fig. 2

Internalization pathways of nucleic acid carriers by receptor-mediated endocytosis. Created with BioRender.com

Fig.3

Optimized trivalent GalNAc-ligand for hepatocyte delivery of direct conjugates with siRNA and ASOs, respectively, via ASGPR-mediated endocytosis. Created with BioRender.com

Fig. 4

Strategies to target different liver cell types: Hepatocytes (orange), hepatic stellate cells (blue), Kupffer cells (purple) and liver sinusoidal endothelial cells (light red). Created with BioRender.com

Fig. 5

Interaction of i.v. injected targeted nanoparticles with blood components and consequences for the delivery process. Formation of protein corona leads to reduced intended targeting ability due to masked ligands. Protein corona may lead to transport to other cells or uptake via receptors recognizing plasma proteins. Additionally, endosomal escape can be hampered by protein layer. Created with BioRender.com

Fig. 6

Strategies to improve or maintain targeting ability in vivo. (A) PEG-Backfilling avoids formation of protein corona, which would mask targeting ligands. Short PEG chains are necessary to maintain accessibility of the ligands [264]. (B) Application of a nanoprimer is reducing off-target LNP uptake by Kupffer cells and LSECs and enhances delivery to hepatocytes. [266]. Reproduced with permission from reference with Copyright © 2020, American Chemical Society. (C) Adjustment of surface chemistry leads to modified protein corona composition and can be used for targeted delivery by altered biodistribution profile. Created with BioRender.com