Oral Delivery of Nucleic Acid Therapies for Local and Systemic Action

Abstract

Nucleic acid (NA) therapy has gained importance over the past decade due to its high degree of selectivity and minimal toxic effects over conventional drugs. Currently, intravenous (IV) or intramuscular (IM) formulations constitute majority of the marketed formulations containing nucleic acids. However, oral administration is traditionally preferred due to ease of administration as well as higher patient compliance. To leverage the benefits of oral delivery for NA therapy, the NA of interest must be delivered to the target site avoiding all degrading and inhibiting factors during its transition through the gastrointestinal tract. The oral route presents myriad of challenges to NA delivery, making formulation development challenging. Researchers in the last few decades have formulated various delivery systems to overcome such challenges and several reviews summarize and discuss these strategies in detail. However, there is a need to differentiate between the approaches based on target so that in future, delivery strategies can be developed according to the goal of the study and for efficient delivery to the desired site. The goal of this review is to summarize the mechanisms for target specific delivery, list and discuss the formulation strategies used for oral delivery of NA therapies and delineate the similarities and differences between local and systemic targeting oral delivery systems and current challenges.

Keywords: gastrointestinal diseases; local target; nucleic acids; oral delivery; systemic target.

Fig. 1

Transport of delivery systems across intestinal membrane. The illustration was created with BioRender.com.

Fig. 2

“Mechanisms of translocation of delivery systems (A) Phagocytosis; (B) Macropinocytosis; (C) Clathrin-dependent endocytosis; (D) Clathrin-independent endocytosis; (E) Caveolae-mediated endocytosis; (F) Direct translocation. Other conventions: IgG, Immunoglobulin G; Fcγ Rec, Fcγ receptor; TfR, Transferrin receptor; Folate-Rec, Folate receptor; LDL-Rec, low-density lipoprotein receptor; EGF-Rec, Epidermal growth factor receptor; ER, Endoplasmatic reticulum.” This figure based on Yameen et al. and Hillaireau et al. was created by Torres-Vanegas et al. [–18]. Copyright 2021, open access, MDPI.

Fig. 3

Local vs systemic action pathway for oral delivery of nucleic acids. The illustration was created with BioRender.com.

Fig. 4

Biodistribution of siRNA in various mouse organs and plasma after oral gavage of TAMRA labeledsiRNA loaded MTC nanoparticles. Reproduced with permission from ref. [34] Copyright 2013, Elsevier.

Fig. 5

tdTomato expression in mice after a direct injection into the stomach submucosa, an IV injection into the tail vein, and no injection of mRNA in mice using flow cytometry Reproduced with permission from ref. [1] Copyright 2013, Elsevier.

Fig. 6

Physiochemical challenges to oral drug delivery of NAs. A) Enzymatic and pH barrier. B) Mucus, peristalsis, and epithelial barrier. The figure was designed using BioRender.com.