The Role of Mucoadhesion and Mucopenetration in the Immune Response Induced by Polymer-Based Mucosal Adjuvants

Abstract

Mucus is a viscoelastic gel that acts as a protective barrier for epithelial surfaces. The mucosal vehicles and adjuvants need to pass through the mucus layer to make drugs and vaccine delivery by mucosal routes possible. The mucoadhesion of polymer particle adjuvants significantly increases the contact time between vaccine formulations and the mucosa; then, the particles can penetrate the mucus layer and epithelium to reach mucosa-associated lymphoid tissues. This review presents the key findings that have aided in understanding mucoadhesion and mucopenetration while exploring the influence of physicochemical characteristics on mucus-polymer interactions. We describe polymer-based particles designed with mucoadhesive or mucopenetrating properties and discuss the impact of mucoadhesive polymers on local and systemic immune responses after mucosal immunization. In future research, more attention paid to the design and development of mucosal adjuvants could lead to more effective vaccines.

Keywords: immune response; mucoadhesion; mucosal adjuvants; mucosal vaccines; polymeric particles.

Figure 1

Components of gut-associated lymphoid tissues. The intestinal epithelium comprises multiple cell types derived from intestinal stem cells (IECs), including absorptive enterocytes, Paneth cells, goblet cells, tuft cells, and enteroendocrine cells. The IECs maintain gut homeostasis by synthesizing and secreting mucins, antimicrobial peptides, hormones, and soluble proteins. Furthermore, the IECs participate in the recognition of microorganisms via PPRs. The inner mucus layer or glycocalyx that lines the intestinal epithelium contains many antimicrobial peptides (AMPs) and IgA, both with effector functions. The outer mucus layer is also colonized by commensal microbiota. AMPs bind to glycosylated proteins, neutralize bacterial toxins, participate in the recruitment of effectors cells, and directly kill bacteria. Antigen uptake can occur by M-cell-mediated transcytosis, via macrophage/dendritic cells extending transepithelial dendrites into the gut lumen, paracellular pathway, or through goblet-cells-associated antigen passages. The passage of the particles is further facilitated by mucoadhesion and mucopenetration phenomena. In gut-associated lymphoid tissues, antigens are presented to naive T and B cells with subsequent antigen-specific immune responses. PPs are mucosa-inductive sites for immune responses in the gastrointestinal tract, while the lamina propria and epithelial compartment constitute effector sites. FAE, follicle associated epithelial; SED, subepithelial dome; PPs, Peyer’s patches; IFR, interfollicular regions; FDC, follicular dendritic cells; Tfh, T follicular helper cells.

Scheme 1

Material types of particulate systems used as mucosal adjuvants. PCL, polycaprolactone; PLGA, poly (lactic-co-glycolide); PGA, poly (α-L-glycolic acid); PLA, poly (lactic acid); γ- PGA, poly (glutamic acid); PEI, polyethyleneimine; VLPs, virus-like particles; MSNs, mesoporous silica nanoparticles; MCNs, mesoporous carbon nanoparticles.

Figure 2

Mucoadhesion of polymeric particles to mucous membranes. First, an intimate interaction between polymeric particles and the mucous membrane occurs in the contact stage, with subsequent wetting and swelling. Later, in the state of consolidation, physicochemical interactions enable the adsorption and molecular interpenetration of polymer chains into the mucus layer that covers the epithelial surface, eventually leading to prolonged adhesion.

Figure 3

Theories of mucoadhesion. The electronic theory describes mucoadhesion mediated by electrostatic forces. Adsorption assumes intermolecular contact at the interface and adhesion of materials by intermolecular forces. Wetting is described in terms of the spreading coefficient; therefore, the requirement for mucoadhesive materials to adhere is that these can spread spontaneously onto a surface. The diffusion theory: interdiffusion and interpenetration through the polymer-mucin interface according to their concentration gradient. Fracture describes the forces required to separate two surfaces after bonding and assumes that adhesion bond failure occurs at the interface (Wad: work adhesion). Mechanical assumes that the irregular rough or abrasive substrate surface provides mechanical keying.