The Macromolecular Interpenetration theory, also known as the diffusion theory, states that the mucoadhesive molecules and mucus glycoproteins mutually interact by means of interpenetration of their chains and the forming of secondary semi-permanent adhesive bonds. It is necessary that the mucoadhesive device has features or properties that favor both chemical and mechanical interactions for the macromolecular interpenetration theory to take place. Molecules that can present mucoadhesive properties are molecules with hydrogen bond building groups, high molecular weight, flexible chains, and surface active properties.
It is perceived that increase in adhesion force is associated with the degree of penetration of polymer chains. Literature states that the degree of penetration required for efficient bioadhesive bonds lies in the range of 0.2-0.5μm. The following equation can be used to estimate the degree of penetration of polymer and mucus chains:
with  as contact time and  as the diffusion coefficient of the mucoadhesive material in the mucus. Maximum adhesion strength is reached when penetration depth is approximately equal to polymer chain size. Properties of mutual solubility and structural similarity will improve the mucoadhesive bond.