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Despite their widespread use, their mode of action remains unknown. Herein, we elucidate how CPDs work using combined data from protein knockdown, \u00b5Map proteomics, coacervate assembly, mechanosensitive fluorescent membrane probes, CPD inhibitors, activators, and depolymerization. Their guanidinium sidechains first ion\u2010pair with anionic clusters on cell surfaces. By enhancing effective CPD concentration, these non\u2010covalent interactions enable, accelerate, and direct dynamic covalent disulfide exchange cascades with cellular thiols and disulfides. CPD bioconjugation rates match their uptake activity, exceeding those of disulfide monomers by 3000 times. Exchange with proteins capable of membrane remodeling allows CPDs to exploit these proteins' primary functions to mobilize anionic lipids (scramblases, ANO6), form toroidal elastic pores and related membrane deformations, and repair all after CPD\u2010SOI conjugates have passed through (tetraspanins, TSPAN8, flippases, etc.). Within cells, CPDs form coacervates and integrate into biological condensates, particularly nucleoli, until they depolymerize and release the SOIs. This understanding of the nature of CPDs also clarifies TMU in general and will guide future efforts to control cellular entry for drug delivery and pathogen defense.<\/jats:p>","DOI":"10.1002\/anie.7902673","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T06:23:33Z","timestamp":1790490213000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Nature of Cell\u2010Penetrating Poly(disulfide)s"],"prefix":"10.1002","author":[{"given":"Saidbakhrom","family":"Saidjalolov","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry University of Geneva  Geneva Switzerland"},{"name":"National Centre of Competence in Research (NCCR) Molecular Systems Engineering  Basel 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