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Additionally, the mucosal layer represents a major yet often overlooked barrier, acting as a dense, heterogenous matrix that traps and limits the diffusion of hydrophobic or charged peptides ( in vitro models, the limitations of which are not fully realized in the current formulation design space ( At the epithelial surface, paracellular transport is restrained by tight junctions, whereas transcellular uptake is constrained by efflux transporters and competition with endogenous substrates (Hamman et al., 2005)