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However, their poor solubility and low bioavailability necessitate high doses and lead to an extremely short\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      half-life. These limitations not only drive the emergence of drug-resistant\n                      <jats:italic toggle=\"yes\">Plasmodium<\/jats:italic>\n                      strains but also compromise long-term therapeutic outcomes. Herein, we report a zein-based sustained release formulation, wherein zein, a natural maize protein, serves as a biocompatible nanocarrier to effectively encapsulate artemisinin (ART). Notably, this nanocarrier formulation achieves a 200-fold enhancement in ART\u2019s water solubility, addressing a key bottleneck of ART-based therapies.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      assays confirm that the zein-based formulation allows for the sustained release of ART, which could help maintain therapeutic concentrations over extended periods and displayed different release rates and good dispersibility in both acid and basic environments. Importantly,\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      evaluations also demonstrate that the nanoformulation exerts potent inhibitory effects against ART-resistant\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      strains in both ring survival assay and recrudescence assay, attributed to the sustained maintenance of effective ART concentrations.\n                      <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                      studies, utilizing both rodent malaria models and humanized erythrocyte mouse models, further validate the nanoformulation\u2019s therapeutic potential. The zein nanocarrier significantly prolongs ART\u2019s\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      half-life via its sustained-release capability, thereby maintaining effective blood concentrations over an extended duration. Compared to free ART, the nanoformulation exhibits superior efficacy in reducing parasitemia, preventing malaria recrudescence, and, most notably, overcoming ART resistance in drug-resistant\n                      <jats:italic toggle=\"yes\">Plasmodium<\/jats:italic>\n                      infections. Collectively, these findings establish the zein-based nanocarrier as a promising strategy to optimize ART-based therapies by addressing solubility and pharmacokinetic limitations while effectively combating drug-resistant malaria.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Half of the world\u2019s population is at risk of malaria infection, and artemisinin (ART) turns out to be a powerful medicine for malaria control. The rapid emergence and global spread of resistance to ART have led to a significantly increasing clinical treatment failure rate worldwide. A critical limitation of ART is its extremely short blood half-life (~1 h), which results in rapid declines in plasma drug concentrations below therapeutic thresholds. Some parasites may switch into a \u201cdormant\u201d form, which is less sensitive to ART, resulting in recrudescence following treatment. Thus, developing a sustained-release formulation provides a promising solution to prolong the\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      half-life of ART. Additionally, its relatively low solubility restricts its\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      bioavailability, primarily due to the limited dissolution and absorption of the compound in aqueous biological environments. In this study, we prepared a zein-based sustained-release formulation of ART for oral and intraperitoneal administration. Our results indicate that this zein-based sustained release nanoformulation not only significantly improves ART\u2019s water solubility (a key barrier to its bioavailability) but also extends its\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      half-life via controlled drug release. Importantly, the prolonged half-life ensures sustained therapeutic ART concentrations, directly enhancing the formulation\u2019s ability against ART-resistant\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      strains. Collectively, these results highlight the formulation\u2019s substantial potential for clinical application in improving ART-based antimalarial therapy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.03696-25","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T14:01:10Z","timestamp":1768226470000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Development and evaluation of novel zein-based artemisinin sustained-release formulation for treating drug-resistant malaria"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3090-2018","authenticated-orcid":false,"given":"Yijie","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04mkzax54","id-type":"ROR","asserted-by":"publisher"}],"name":"The Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1339-3558","authenticated-orcid":false,"given":"Xinyu","family":"Yu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01czqbr06","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health, School of Public Health, Nanjing Medical University","place":["Nanjing, China"]},{"id":[{"id":"https:\/\/ror.org\/01d176154","id-type":"ROR","asserted-by":"publisher"}],"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01czqbr06","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health, School of Public Health, Nanjing Medical University","place":["Nanjing, China"]},{"id":[{"id":"https:\/\/ror.org\/01d176154","id-type":"ROR","asserted-by":"publisher"}],"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"He","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01d176154","id-type":"ROR","asserted-by":"publisher"}],"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxin","family":"Tang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01czqbr06","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health, School of Public Health, Nanjing Medical University","place":["Nanjing, China"]},{"id":[{"id":"https:\/\/ror.org\/01d176154","id-type":"ROR","asserted-by":"publisher"}],"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Fang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01d176154","id-type":"ROR","asserted-by":"publisher"}],"name":"National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases","place":["Wuxi, China"]},{"name":"Xishan People\u2019s Hospital of Wuxi City, Wuxi Branch of Zhongda Hospital Southeast University","place":["Wuxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Culleton","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017hkng22","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Parasitology, Proteo-Science Centre, Ehime University","place":["Matsuyama, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8759-9102","authenticated-orcid":true,"given":"Qingfeng","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03rc6as71","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Parasitology, State Key Laboratory of Cardiology and Research Center for Translational Medicine, Shanghai East Hospital; 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