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Nanobodies, due to their many unique properties, are emerging as powerful imaging agents; however, conventional non\u2010specific conjugation strategies often yield heterogeneous products that limit in vivo performance. Here, we report a chemoenzymatic strategy that enables precise and modular assembly of nanobody conjugates using farnesyltransferase (FTase)\u2010mediated site\u2010specific modification. We developed a trifunctional FTase substrate that introduces two orthogonal bioorthogonal handles, an aldehyde and an azide, onto nanobodies in a single enzymatic step. These handles enable independent and controlled conjugation of imaging payloads (fluorophores or radioisotopes) and pharmacokinetic modifiers (i.e. PEG), which enhance in vivo signal\u2010to\u2010noise ratios. Applying this strategy to nanobodies targeting CD45 and CD11b, markers broadly expressed on all immune cells and myeloid subsets, respectively, we generated well\u2010defined, dually modified constructs that enabled high\u2010contrast in vivo visualization of immune organs, including the spleen and lymph nodes. In a mouse model of localized inflammation, these probes robustly delineated inflamed tissue with high sensitivity and specificity. Together, this FTase\u2010enabled dual\u2010labeling approach provides a versatile and generalizable platform for the rapid generation of precisely defined nanobody\u2010based imaging agents, advancing non\u2010invasive detection and monitoring of inflammation across diverse disease contexts.<\/jats:p>","DOI":"10.1002\/anie.5009703","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T16:28:27Z","timestamp":1787588907000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Farnesyltransferase Enables Modular Assembly of Dual\u2010Functional Nanobody Conjugates for in Vivo Imaging of Inflammation"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6257-8874","authenticated-orcid":false,"given":"Sneha","family":"Venkatachalapathy","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Minnesota  Minneapolis Minnesota 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