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CD28, a costimulatory receptor aberrantly overexpressed on T\u2010ALL cells, presents a promising underexplored therapeutic target. In this study, we developed an enzyme\u2010responsive self\u2010assembling peptide, SA\n                    <jats:sup>p<\/jats:sup>\n                    \u2010CD28, designed to target CD28 and undergo receptor\u2010mediated self\u2010assembly in the tumor microenvironment. Upon dephosphorylation by overexpressed phosphatases, SA\n                    <jats:sup>p<\/jats:sup>\n                    \u2010CD28 transitions from an \u03b1\u2010helix to a \u03b2\u2010sheet\/\u03b2\u2010turn rich structure, facilitating the formation of nanooligomers that engage CD28 and activate cytotoxic pathways. Transcriptomic and biochemical analyses reveal that SA\n                    <jats:sup>p<\/jats:sup>\n                    \u2010CD28 induces a profound dysregulation of CD28 downstream signaling, characterized by the suppression of the PLC\u03b3 and Akt pathways. These signaling perturbations lead to oxidative stress and disruption of intracellular calcium homeostasis, resulting in calcium overload, calpain activation, and cytoskeletal collapse. Besides, confocal imaging suggested that the peptide self\u2010assembly can enter the nucleus and disrupt it. In Jurkat xenograft models, SA\n                    <jats:sup>p<\/jats:sup>\n                    \u2010CD28 demonstrated potent antitumor activity, and its combination with cytarabine resulted in near\u2010complete tumor suppression, highlighting its potential for T\u2010ALL treatment. This work introduces a CD28\u2010targeted, enzyme\u2010activated nanotherapeutic strategy that synergizes biochemical and mechanical mechanisms to selectively eliminate T\u2010ALL cells. This multi\u2010mechanistic tumor\u2010killing strategy can also be extended to inspire therapeutic approaches for other diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520963","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T18:59:58Z","timestamp":1775156398000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CD28\u2010Targeted Enzyme\u2010Responsive Conformation\u2010Switching Peptide Self\u2010Assembly for Selective T\u2010Cell Acute Lymphoblastic Leukemia (T\u2010ALL) Therapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Jun","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Jia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dekun","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2615-4900","authenticated-orcid":false,"given":"Zhi\u2010Wen","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7710-0155","authenticated-orcid":false,"given":"Yinghao","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengkun","family":"Tuo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2464-839X","authenticated-orcid":false,"given":"Man\u2010Di","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University  Tianjin P. R. 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