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. I′ve been slimed! Densely PEGylated nanoparticles can rapidly diffuse across mucus but fail to specifically bind the underlying cells. By engineering a novel PEG‐binding bispecific antibody, a two‐step pretargeting approach was developed to increase the delivery of PEG‐coated mucus‐penetrating particles (PEG‐MPPs) to mucus‐covered epithelium. [ABSTRACT FROM AUTHOR]