One of the most exciting and challenging applications of nanotechnology in medicine is the development of nanocarriers for the intraepithelial delivery of biomacromolecules through mucosal surfaces. These biomacromolecules represent an increasingly important segment of the therapeutic arsenal; however, their potential is still limited by their instability and inability to cross biological barriers. Nanoparticle carriers have emerged as one of the most promising technologies to overcome this limitation, owing mainly to their demonstrated capacity to interact with biological barriers. In this review, we summarize the current advances made on nanoparticles designed for transmucosal delivery. Supported by the examples of a variety of therapeutic macromolecules – peptides and proteins, gene medicines and vaccines – we review the lessons learned from the past and we offer a future perspective for this field.