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In this study, we evaluate a modular strategy for organelle\u2010directed delivery based on organelle\u2010targeting groups combined with tetrazine\u2010\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010cyclooctene bioorthogonal chemistry. We demonstrate that organelle\u2010targeting probes bearing tetrazine or\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010cyclooctene can efficiently undergo inverse\u2010electron\u2010demand Diels\u2010Alder reactions within various cellular compartments, including the plasma membrane, mitochondria, nucleus, endoplasmic reticulum, and lysosomes. Using this method, we localize fluorophores and the cytotoxic drug doxorubicin to specific organelles in living cells. We further show that tetrazine\u2010 or\n                    <jats:italic>trans<\/jats:italic>\n                    \u2010cyclooctene\u2010modified doxorubicin prodrugs restore cytotoxic activity upon click\u2010to\u2010release activation inside cells. However, direct comparisons of different probe architectures revealed that organelle targeting and reaction efficiency are highly sensitive to structural context, cargo type, and subcellular environment, and cannot be predicted solely from targeting motifs. Overall, these findings establish a framework for comparing organelle\u2010targeted bioorthogonal chemistry and offer practical guidance for designing probes and prodrugs that enable precise spatiotemporal control of small\u2010molecule activity in living cells.\n                  <\/jats:p>","DOI":"10.1002\/chem.71198","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T01:54:43Z","timestamp":1780365283000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Organelle\u2010Resolved Tetrazine\u2010\n                    <i>trans<\/i>\n                    \u2010Cyclooctene Click Chemistry for Cargo Delivery and Release"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9206-4092","authenticated-orcid":false,"given":"Oleh","family":"Durydivka","sequence":"first","affiliation":[{"name":"Department of Bioorganic and Medicinal Chemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4378-7934","authenticated-orcid":false,"given":"Marek","family":"Chovanec","sequence":"additional","affiliation":[{"name":"Department of Bioorganic and Medicinal Chemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rastislav","family":"Dzijak","sequence":"additional","affiliation":[{"name":"Department of Bioorganic and Medicinal Chemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Rahm","sequence":"additional","affiliation":[{"name":"Department of Bioorganic and Medicinal Chemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jachym","family":"Hrusak","sequence":"additional","affiliation":[{"name":"Department of Bioorganic and Medicinal Chemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6325-8936","authenticated-orcid":false,"given":"Paul E.","family":"Reyes\u2010Gutierrez","sequence":"additional","affiliation":[{"name":"Department of Bioorganic and Medicinal Chemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6633-4351","authenticated-orcid":false,"given":"Milan","family":"Vrabel","sequence":"additional","affiliation":[{"name":"Department of Bioorganic and Medicinal Chemistry Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"crossref","unstructured":"D. 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