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However, the efficiency of this process is often constrained by the hypoxic conditions in tumor tissues. To address this limitation, we developed a mitochondria-targeted PFAGD nanogel, by covalently conjugating ferrocene (Fc) and GOx onto a polyethylenimine (PEI) backbone and encapsulating atovaquone (ATO), a mitochondrial respiration inhibitor. Surface modification with DNA-TPP enabled mitochondrial targeting. The incorporated ATO effectively alleviated intracellular hypoxia, thereby promoting the GOx\/Fc-mediated cascaded Fenton reaction. This process drove substantial ROS (particularly \u00b7OH) generation, thereby amplifying chemodynamic therapy. Multiple cellular assays confirmed that the three-step cascade reaction in the PFAGD nanogel enhanced the proliferation inhibition effect on cancer cells, especially under hypoxic conditions. This self-reinforcing nanoplatform mitigates tumor hypoxia and enables sustained, localized ROS generation, offering a promising strategy for catalytic anticancer therapy.<\/jats:p>","DOI":"10.1021\/acs.biomac.5c02460","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:56:23Z","timestamp":1783529783000},"page":"5040-5054","source":"Crossref","is-referenced-by-count":0,"title":["Cascade-Enhanced Chemodynamic Therapy via a Mitochondria-Targeted\nPEI-Fc-Gox Nanogel with Dual Antihypoxia and ROS Amplification"],"prefix":"10.1021","volume":"27","author":[{"given":"Shuhao","family":"Wang","sequence":"first","affiliation":[{"name":"Wuhan University of Science and Technology , , ,","place":["Wuhan, China, 430081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengwei","family":"Yan","sequence":"additional","affiliation":[{"name":"Wuhan University of Science and Technology , , ,","place":["Wuhan, China, 430081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongze","family":"Duan","sequence":"additional","affiliation":[{"name":"Wuhan University of Science and Technology , , ,","place":["Wuhan, China, 430081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Lv","sequence":"additional","affiliation":[{"name":"Wuhan University of Science and Technology , , ,","place":["Wuhan, China, 430081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-4833","authenticated-orcid":true,"given":"Simin","family":"Liu","sequence":"additional","affiliation":[{"name":"Wuhan University of Science and Technology , , ,","place":["Wuhan, China, 430081"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4537-110X","authenticated-orcid":true,"given":"Zhiyong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Wuhan University of Science and Technology , , ,","place":["Wuhan, China, 430081"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"2026081008072449500_cit1","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1002\/anie.201805664","article-title":"Chemodynamic therapy: Tumour microenvironment-mediated\nFenton and Fenton-like reactions","volume":"58","author":"Tang","year":"2019","journal-title":"Angew. 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