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Recently, a synthetic biostatic state in mammalian cells is achieved via intracellular network formation using bio\u2010orthogonal strain\u2010promoted azide\u2010alkyne cycloaddition (SPAAC) reactions between functionalized poly(ethylene glycol) (PEG) macromers. In this work, the effects of intracellular network formation on a 3D epithelial MCF10A spheroid model are explored. Macromer\u2010transfected cells are encapsulated in Matrigel, and spheroid area is reduced by \u224850% compared to controls. The intracellular hydrogel network increases the quiescent cell population, as indicated by increased p21 expression. Additionally, bioenergetics (ATP\/ADP ratio) and functional metabolic rates are reduced. To enable reversibility of the biostasis effect, a photosensitive nitrobenzyl\u2010containing macromer is incorporated into the PEG network, allowing for light\u2010induced degradation. Following light exposure, cell state, and proliferation return to control levels, while SPAAC\u2010treated spheroids without light exposure (i.e., containing intact intracellular networks) remain smaller and less proliferative through this same period. These results demonstrate that photodegradable intracellular hydrogels can induce a reversible slow\u2010growing state in 3D spheroid culture.<\/jats:p>","DOI":"10.1002\/adhm.202302528","type":"journal-article","created":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T01:41:01Z","timestamp":1703382061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Reversible Intracellular Gelation of MCF10A Cells Enables Programmable Control Over 3D Spheroid Growth"],"prefix":"10.1002","volume":"13","author":[{"given":"Delaney L.","family":"McNally","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder  Boulder CO 80303 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Macdougall","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder  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