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However, conventional agents often suffer from nonspecific activation and uncontrolled pharmacokinetics, which limit their ability to achieve precise theranostics. To address this, we present an ultra\u2010specific in situ activatable platform for tumor phototheranostics that integrates controlled pretargeting via in situ self\u2010assembly with bioorthogonal reaction\u2010mediated activation. This platform consists of two key components: a cathepsin B and glutathione dual\u2010responsive pretargeting agent, Val\u2010Cit\u2010Cys(StBu)\u2010Lys(Tz)\u2010CBT (CBT\u2010Tz), which undergoes tumor microenvironment\u2010triggered self\u2010assembly into nanoaggregates, leading to localized accumulation of tetrazine (Tz) groups; and a vinyl ether\u2010caged and PEGylated hemicyanine (PEG\u2010hCy\u2010VE) as an activatable theranostic agent, which can be uncaged via a bioorthogonal activation with the pre\u2010accumulated Tz groups. This reaction restores near\u2010infrared fluorescence and activates potent PDT activity selectively at the tumor site. The pretargeting strategy, coupled with the activation approach, provides superior spatiotemporal control, enabling simultaneous high\u2010contrast fluorescence imaging and spatially precise PDT. Guided by real\u2010time imaging, personalized PDT was implemented, leading to effective tumor suppression with minimal systemic toxicity. By synergizing in situ self\u2010assembly and bioorthogonal activation, this work provides a robust, extensible, and highly specific platform for precise drug delivery and heterogeneous tumor theranostics.<\/jats:p>","DOI":"10.1002\/adhm.71328","type":"journal-article","created":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T04:40:12Z","timestamp":1780807212000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Controlled In Situ Self\u2010Assembly for Pretargeted Tumor Theranostics via Bioorthogonal Activation"],"prefix":"10.1002","volume":"15","author":[{"given":"Pan","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Chemistry Beijing University of Technology  Beijing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Chemistry Beijing University of Technology  Beijing P. R. 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