Engineering drug delivery systems to overcome mucosal barriers for immunotherapy and vaccination

Abstract

Mucosal surfaces protect our bodies from pathogens and external irritants using a system of biological barriers. Overcoming these barriers is a significant drug delivery challenge, particularly for immunotherapies that aim to modulate the local immune response. Reaching local lymphoid tissues and draining lymph nodes (LNs) requires crossing the mucus mesh, mucosal epithelium, and either targeting M cells covering lymphoid tissues or utilizing lymphatic transport that shuttles molecules and particulates from the periphery to the LN. We first highlight the barrier properties of mucus and mucosal epithelium, and the function of the mucosal immune system. We then dive into existing drug delivery technologies that have been engineered to overcome each of these barriers. We particularly focus on novel strategies for targeting lymphoid tissues, which has been shown to enhance immunotherapies and vaccinations, via directly targeting LNs, lymphatic vessels, and M cells that transport samples of mucosal content to the lymphoid tissues.

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

“…In addition to the glycosylated regions, the mucin peptides may also trap hydrophobic particulates ( Fig. 4 ) 72 , 78 , 79 , 80 , 81 . Favorably, an enhanced mucoadhesion could prolong the lung retention time of pulmonary delivered particles, leading to an improved and pharmacokinetic profile 75 .…”

Targeting the Gut Mucosal Immune System Using Nanomaterials

“…The overall negative charge of mucins allows for electrostatic interactions with positively charged pathogens or particulates and thus traps them. Further, the mucin fibers have hydrophobic regions that interact to form bundles that can trap hydrophobic materials [4]. Mucin fibers also link with each other leading to a mesh-like structure, thus allowing exclusion based on size of particulates.…”

“…Mucin fibers also link with each other leading to a mesh-like structure, thus allowing exclusion based on size of particulates. Mucus composition can vary significantly in structure and thickness at different mucosal surfaces and in different sections of the GI tract [4]. Crossing the mucus barrier poses a significant hurdle for delivering therapeutics to the mucosal surfaces, including the GI tract, and has been the focus of several other excellent reviews [4,5].…”

Cellular Immunotherapy and the Lung

“…Mucosal surfaces are the largest organs that protect our internal body surfaces from being exposed to the outside environment. They also prohibit pathogens and macromolecules from reaching the internal surfaces of the body when their entry is unfavourable [5,6]. The mucosal surfaces of the lungs and upper respiratory tract are frequently susceptible to infection [7].…”

“…The physical mucus layer covering the mucosal epithelium, mucosal immune cells, lymphoid organs and underlying blood and lymphatic vasculature, along with the local immune system, act as a barrier against pathogens. However, these aforementioned barriers present an issue for CIs which must first pass through the mucus and epithelium before arriving at their localised therapeutic target [6]. It is well known that the induction of mucosal immunity via vaccination is a challenging task, and it often requires specific delivery systems and adjuvants for optimal efficacy [9].…”