Mucus-penetrating nanocarriers for the enhanced oral delivery of antibody drugs

Monoclonal antibodies have transformed the treatment of cancer, autoimmune and inflammatory diseases, and other chronic conditions due to their high target specificity and favorable therapeutic profiles. However, nearly all approved antibody therapies require parenteral administration because the gastrointestinal tract presents formidable barriers to oral delivery. Although considerable research has focused on protecting antibodies from degradation and enhancing epithelial transport, the gastrointestinal mucus layer is an often-overlooked determinant of oral bioavailability. As the first extracellular barrier encountered by orally administered formulations, mucus regulates particle diffusion, retention, and clearance, potentially preventing therapeutic antibodies from reaching the epithelial surface. Recent advances in nanotechnology have enabled mucus-permeating delivery systems that minimize interactions with mucins while preserving antibody stability and facilitating epithelial transport. These include PEGylated, zwitterionic, biomimetic, charge-switching, lipid- and polymer-based nanocarriers, as well as multifunctional platforms integrating mucus penetration with controlled release and targeted cellular uptake.This review provides a comprehensive overview of the structural and physiological characteristics of the gastrointestinal mucus barrier and examines how its complex architecture influences the transport of antibody-loaded nanocarriers. Current design principles for mucus-permeating oral delivery systems are discussed, highlighting recent preclinical advances and the key biological and technological challenges limiting clinical translation.[PubMed, Scopus, Google Scholar, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform (ICTRP); January 2001-December 2026].