Paracellular permeability throughout epithelial and endothelial cells is, largely, regulated by apical intercellular junctions additionally known as tight junctions (TJs). These junctions contribute to the spatial definition of various tissue compartments inside organisms, separating them from the skin world in addition to from interior compartments, with their major physiological position of sustaining tissue homeostasis. TJs prohibit the free, passive diffusion of ions and hydrophilic small molecules by way of paracellular clefts and are essential for applicable cell polarization and transporter protein localisation, supporting the managed transcellular diffusion of smaller and bigger hydrophilic in addition to hydrophobic substances. This conventional diffusion barrier idea of TJs has been challenged currently, owing to a greater understanding of the parts which might be related to TJs. It’s now well-established that mutations in TJ proteins are related to a spread of human ailments and {that a} change within the membrane fluidity of neighbouring cells can open prospects for therapeutics to cross intercellular junctions. Nanotechnological approaches, exploiting ultrasound or hyperosmotic brokers and permeation enhancers, are the paradigm for reaching enhanced paracellular diffusion. The opposite broadly used transport route of medication is through transcellular transport, permitting the passage of quite a lot of pro-drugs and nanoparticle-encapsulated medicine through completely different mechanisms based mostly on receptors and others. For a very long time, there was an expectation that lipidic nanocarriers and polymeric nanostructures might revolutionize the sector for the supply of RNA and protein-based therapeutics throughout completely different organic limitations outfitted with TJs (e.g., blood–mind barrier (BBB), retina–blood barrier (RBB), corneal TJs, and so on.). Nonetheless, solely a restricted enhance in therapeutic effectivity has been reported for many techniques till now. The aim of this evaluate is to discover the explanations behind the present failures and to look at the emergence of artificial and cell-derived nanomaterials and nanotechnological approaches as potential game-changers in enhancing drug supply to focus on places each at and throughout TJs utilizing modern ideas. Particularly, we are going to concentrate on latest developments in numerous nanotechnological methods enabling the bypassing or temporally opening of TJs to the mind and to the retina, and talk about their benefits and limitations.