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Although\n                      <jats:italic>Angelica sinensis<\/jats:italic>\n                      polysaccharide (ASP) has shown protective effects against MI\/RI, its clinical translation remains limited due to poor bioavailability and low target specificity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To address these limitations, we developed ASP@PLGA-PEG nanoparticles using a solvent evaporation method and characterized their morphology, size distribution, and surface charge by transmission electron microscopy, dynamic light scattering, and zeta potential analysis. The protective effects of ASP@PLGA-PEG were first evaluated in HL-1 cardiomyocytes subjected to oxygen\u2013glucose deprivation\/reoxygenation (OGD\/R) by assessing cell viability, mitochondrial membrane potential, ROS generation, lipid peroxidation, and antioxidant capacity. An ex vivo MI\/RI model was then established using a Langendorff isolated heart perfusion system to assess hemodynamic function, infarct size, histopathology, and mitochondrial ultrastructure. In addition, an in vivo mouse MI\/R model induced by LAD ligation\u2013reperfusion was used to evaluate cardiac function, infarct size, serum injury markers, oxidative stress, and ferroptosis-\/ER stress\u2013related proteins. Finally, siRNA-mediated ATF6 knockdown was performed in HL-1 cells to determine whether the protective and anti-ferroptotic effects of ASP@PLGA-PEG are ATF6 dependent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ASP@PLGA-PEGnanoparticles significantly reduced oxidative stress, improved cardiomyocyteviability, and inhibited ferroptosis in OGD\/R-injured HL-1 cells. In theLangendorff model, ASP@PLGA-PEG treatment effectively decreased myocardialinfarct size, preserved cardiac hemodynamics, and alleviated structural damage.Consistently, in vivo administration of ASP@PLGA-PEG markedly improved leftventricular systolic function, reduced infarct size and serum LDH levels, preserved mitochondrial and histologicalintegrity, and restored redox homeostasis in MI\/R hearts. Mechanistically,ASP@PLGA-PEG nanoparticles activated ATF6 signaling and attenuated ER stress,while suppressing NCOA4-mediated ferritinophagy, thereby limiting iron overloadand lipid peroxidation to protect cardiomyocytes against ferroptosis duringMI\/RI. Importantly, ATF6 knockdown largely abrogated the effects ofASP@PLGA-PEG on NCOA4\/FTH1 expression, ROS production, and lipid peroxidation,indicating that these protective actions are critically ATF6 dependent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Thisstudy demonstrates that ASP@PLGA-PEG nanoparticles exert potentcardioprotective effects in vitro, ex vivo, and in vivo through a multi-targetmechanism involving ER stress modulation, enhancement of antioxidativedefenses, and inhibition of ferritinophagy-driven ferroptosis. These findingshighlight ASP@PLGA-PEG as a promising nanomedicine strategy for the preventionand treatment of myocardial ischemia\u2013reperfusion injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-07752-8","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T09:07:38Z","timestamp":1772096858000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Angelica sinensis polysaccharide nanoparticles can improve myocardial ischemia-reperfusion injury by inhibiting ferritinophagy via the ATF6\/NCOA4 pathway"],"prefix":"10.1186","volume":"24","author":[{"given":"Cheng","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maomao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"7752_CR1","doi-asserted-by":"crossref","unstructured":"Mastoor Y, Murphy E, Roman B. 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