<p>Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse group of natural products. The lasso peptide class of RiPPs adopt a unique [1]rotaxane conformation formed by a lasso cyclase, conferring diverse bioactivities and remarkable stability. The prediction of lasso peptide properties, such as substrate compatibility with a particular lasso cyclase or desired biological activity, remains challenging due to limited experimental data and the complexity of substrate fitness landscapes. Here, we develop LassoESM, a tailored language model that improves lasso peptide property prediction. LassoESM embeddings enable accurate prediction of substrate compatibility, facilitate identification of novel non-cognate cyclase–substrate pairs, and enhance prediction of RNA polymerase inhibitory activity, a biological activity of several known lasso peptides. We anticipate that LassoESM and future iterations will be instrumental in the rational design and discovery of lasso peptides with tailored functions.</p>