Engineering Polymer‐Binding Bispecific Antibodies for Enhanced Pretargeted Delivery of Nanoparticles to Mucus‐Covered Epithelium

Mucus represents a major barrier to sustained and targeted drug delivery to mucosal epithelium. Ideal drug carriers should not only rapidly diffuse across mucus, but also bind the epithelium. Unfortunately, ligand‐conjugated particles often exhibit poor penetration across mucus. In this work, we explored a two‐step “pretargeting” approach through engineering a bispecific antibody that binds both cell‐surface ICAM‐1 and polyethylene glycol (PEG) on the surface of nanoparticles, thereby effectively decoupling cell targeting from particle design and formulation. When tested in a mucus‐coated Caco‐2 culture model that mimics the physiological process of mucus clearance, pretargeting increased the amount of PEGylated particles binding to cells by around 2‐fold or more compared to either non‐targeted or actively targeted PEGylated particles. Pretargeting also markedly enhanced particle retention in mouse intestinal tissues. Our work underscores pretargeting as a promising strategy to improve the delivery of therapeutics to mucosal surfaces. Schleimige Angelegenheit: Dicht PEGylierte Nanopartikel können rasch durch Schleim diffundieren, jedoch nicht spezifisch an darunterliegende Zellen binden. Auf Basis eines neuartigen, künstlichen PEG‐bindenden bispezifischen Antikörpers wurde ein zweistufiger Pretargeting‐Ansatz entwickelt, um den Transport PEG‐bedeckter, schleimdurchdringender Partikel (PEG‐MPPs) zu schleimbedecktem Epithel zu erhöhen.