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Current strategies to develop conditionally active cytokines involve complex engineering and production, limiting their application to a select few cytokines and receptors. Here, we describe a simple, highly modular format called Sterically Masked Activated Cytokine (SMACk) via facile assembly of a targeting Fab\/VHH, cytokine, and Fc. We first develop an interleukin-22 (IL-22) SMACk selective for intestinal epithelial cells, wherein the Fab\/VHH serves a dual masking and targeting role. Detailed analysis revealed a\n                    <jats:italic toggle=\"yes\">cis<\/jats:italic>\n                    signaling mechanism via a reduced on-rate and identified tunable format parameters. In mice, the IL-22-SMACk showed selective activity in the colon and efficacy in a colitis model. Finally, we highlight the versatility of SMACks by selectively directing interferon-\u03b1, IL-2, IL-4, or IL-7 to CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, underscoring the potential of this platform to advance cytokine research and therapies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2513720123","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T18:07:16Z","timestamp":1774462036000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["A modular platform for Sterically Masked Activated Cytokines (SMACks)"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2634-8470","authenticated-orcid":false,"given":"Travis J.","family":"Morgenstern","sequence":"first","affiliation":[{"name":"Department of Antibody Engineering, Genentech Inc.","place":["South San 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