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Herein, a bioactive self\u2010delivering \u201cSplit Nano\u2010Assembly of Photosensitizers and Targeting Chimeras\u201d (SNAP\u2010TAC) theranostic platform is developed to address these challenges and enable tumor\u2010selective synergistic photo\u2010immunotherapy. To ensure synchronized in vivo delivery, an intact BRD4 degrader is chemically split into a hydrophobic targeting precursor and an amphiphilic photosensitizer\u2010conjugated peptide, which spontaneously co\u2010assemble into discrete nanoparticles. Within the tumor microenvironment (TME), elevated cathepsin B and glutathione trigger dual\u2010responsive peptide cleavage and disulfide reduction. This unloads the bulky photosensitizer and exposes the reactive 1,2\u2010aminothiol motifs, driving the in situ bioorthogonal synthesis of the active PROTAC via metal\u2010free CBT\u2010Cys click condensation. Consequently, active degraders are preferentially generated in tumor\u2010associated environments. Additionally, the intrinsic fluorescence of the photosensitizer enables real\u2010time fluorescence tracking in vivo to guide localized therapy. Therapeutically, upon localized irradiation, the released photosensitizer induces immunogenic cell death, which synergizes with BRD4 depletion\u2010mediated PD\u2010L1 downregulation and immune\u2010pathway modulation to activate anti\u2010tumor immunity. In vivo evaluations demonstrate that this synergy effectively remodels the suppressive \u201ccold\u201d TME into a cytolytic \u201chot\u201d phenotype. Ultimately, this chemical biology approach effectively addresses the intrinsic selectivity and delivery limitations of conventional PROTACs.<\/jats:p>","DOI":"10.1002\/advs.77938","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Situ Bioorthogonal Synthesis of PROTACs via Dual\u2010Responsive Cleavage for Synergistic Photo\u2010Immunotherapy"],"prefix":"10.1002","author":[{"given":"Shiqin","family":"Jian","sequence":"first","affiliation":[{"name":"School of Medicine Department of Chemistry College of Sciences Shanghai University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiasha","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medicine Department of Chemistry College of Sciences Shanghai University  Shanghai 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