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Therefore, a combination of multiple treatments is becoming more common in oncotherapy. Chemotherapy combined with the induction of ferroptosis is a potential new oncotherapy. Furthermore, polymeric nanoparticles (NPs) can improve the antitumor efficacy and decrease the toxicity of drugs. Herein, a polymeric NP, mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox, is synthesized to decrease the toxicity of doxorubicin (Dox) and enhance the efficacy of chemotherapy by combining it with the induction of ferroptosis. First, mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox is oxidized by endogenous H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> and releases Dox, which leads to an increase of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> by breaking the redox balance. The Fe(II) group of ferrocene converts H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> into \u00b7OH, inducing subsequent ferroptosis. Furthermore, glutathione peroxidase 4, a biomarker of ferroptosis, is suppressed and the lipid peroxidation level is elevated in cells incubated with mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox compared to those treated with Dox alone, indicating ferroptosis induction by mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox. In vivo, the antitumor efficacy of mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox is higher than that of free Dox. Moreover, the loss of body weight in mice treated mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox is lower than in those treated with free Dox, indicating that mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox is less toxic than free Dox. In conclusion, mPEG<jats:italic>\u2010b\u2010<\/jats:italic>PPLGFc@Dox not only has higher antitumor efficacy but it reduces the damage to normal tissue.<\/jats:p>","DOI":"10.1002\/smll.202205024","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T09:37:33Z","timestamp":1668764253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Ferrocene\u2010Based Polymeric Nanoparticles Carrying Doxorubicin for Oncotherapeutic Combination of Chemotherapy and Ferroptosis"],"prefix":"10.1002","volume":"19","author":[{"given":"Jundong","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Urology The Second Affiliated Hospital School of Medicine South China University of Technology  Guangzhou 510180 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huikang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiology The 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