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A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug \u03b4\u2010aminolevulinic acid (\u03b4\u2010ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual\u2010targeting \u03b4\u2010ALA@FMMSH\u2010TPP\u2010TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT\/CDT. Esterase overexpression in OSCC cells triggers \u03b4\u2010ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT\/CDT\u2010induced apoptosis generates \u03b4\u2010ALA\u2010containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, \u03b4\u2010ALA@FMMSH\u2010TPP\u2010TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment.<\/jats:p>","DOI":"10.1002\/adhm.202304639","type":"journal-article","created":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T09:43:40Z","timestamp":1713606220000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cascade Nanoreactor Employs Mitochondrial\u2010Directed Chemodynamic and \u03b4\u2010ALA\u2010Mediated Photodynamic Synergy for Deep\u2010Seated Oral Cancer Therapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Qiqi","family":"Yin","sequence":"first","affiliation":[{"name":"School of Chemical Engineering and Technology Shaanxi Key Laboratory of Energy Chemical Process Intensification Institute of Polymer Science in Chemical Engineering Xi'an Jiaotong University  Xi'an 710049 P. R. 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