Abstract: Provided are single-domain antibodies (sdAbs), also called heavy-chain-only variable domains (VHHs) or camelids, that contain reactive, non-canonical amino acids (ncAAs) and crosslink to target antigen protein. The target antigen may be a toxin or a neurotoxin produced by a pathogenic organism or microorganism that causes or is associated with a disease or pathology. Compositions and methods using the reactive ncAA-containing sdAbs to treat subjects afflicted with a pathology caused by a toxin- or neurotoxin-producing pathogen, such as Botulinum, are provided. In some cases, the compositions and methods comprising the sdAbs treat or prevent intoxication and inhibit and/or neutralize toxin or neurotoxin activity.