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However, phototheranostic prodrugs with dual organelle\u2010targeting and synergistic effects are still rare due to low intelligence of their structures. Besides, the cell membrane, exocytosis, and diffusional hindrance by the extracellular matrix reduce drug uptake. Moreover, the up\u2010regulation of heat shock protein and short singlet\u2010oxygen lifetime in cancer cells hamper photo\u2010ablation efficacy, especially in the mono\u2010therapeutic model. To overcome those obstacles,\u00a0we prepare an esterase\u2010activated DM nano\u2010prodrug, which is conjugated by diiodine\u2010substituted fluorogenic malachite green derivative (MG\u20102I) and phototherapeutic agent DPP\u2010OH via hydrolyzable ester linkage, having pH\u2010responsiveness and genetically targetable activity for dual organelles\u2010targeting to optimize photo\u2010ablation efficacy. The DM nanoparticles (NPs) present improved pH\u2010responsive photothermal\/photodynamic property by the protonation of diethylaminophenyl units in acidic environment. More importantly, the MG\u20102I and DPP\u2010OH moieties can be released from DM nano\u2010prodrug through overexpressed esterase; then specifically target lysosomes and mitochondria in CT\u201026 Mito\u2010FAP cells. Hence, near\u2010infrared DM NPs can trigger parallel damage in dual\u2010organelles with strong fluorescence and effective phototoxicity, thus inducing serious mitochondrial dysfunction and apoptotic death, showing excellent photo\u2010ablation effect based on esterase\u2010activated, pH\u2010responsive, and genetically targetable activities.<\/jats:p>","DOI":"10.1002\/smll.202207535","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T03:23:00Z","timestamp":1676863380000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Esterase\u2010Activated, pH\u2010Responsive, and Genetically Targetable Nano\u2010Prodrug for Cancer Cell Photo\u2010Ablation"],"prefix":"10.1002","volume":"19","author":[{"given":"Pingping","family":"Liang","sequence":"first","affiliation":[{"name":"School of Life Sciences Anhui Medical University  Hefei Anhui 230032 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