Chiseon Ryu,1 Hwangjae Lee,1 Hohyeon Kim,2 Seong Hwang,1 Yaser Hadadian,2,3 Ayeskanta Mohanty,4 In-Kyu Park,4 Beongki Cho,1 Jungwon Yoon,2,3 Jae Young Lee1 1School of Materials Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea; 2School of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea; 3Research Center for Nanorobotics in Brain, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea; 4Department of Biomedical Sciences, Chonnam National University Medical School, Hwasun-gun, Jeollanam-do, Republic of KoreaCorrespondence: Jungwon Yoon; Jae Young Lee Tel +82 62 715 5332; +82 62 715 2358Email jyoon@gist.ac.kr; jaeyounglee@gist.ac.krIntroduction: Iron oxide magnetic nanoparticles (IONPs) have attracted considerable attention for various biomedical applications owing to their ease of synthesis, strong magnetic properties, and biocompatibility. In particular, IONPs can generate heat under an alternating magnetic field, the effects of which have been extensively studied for magnetic hyperthermia therapy. However, the development of IONPs with high heating efficiency, biocompatibility, and colloidal stability in physiological environments is still required for their safe and effective application in biomedical fields.Methods: We synthesized magnetic IONP/polymer nanocomposites (MNCs) by embedding IONPs in a poly(L-lactic acid) (PLA) matrix via nanoemulsion. The IONP contents (Fe: 9– 22 [w/w]%) in MNCs were varied to investigate their effects on the magnetic and hyperthermia performances based on their optimal interparticle interactions. Further, we explored the stability, cytocompatibility, biodistribution, and in vivo tissue compatibility of the MNCs.Results: The MNCs showed enhanced heating efficiency with over two-fold increase compared to nonembedded bare IONPs. The relationship between the IONP content and heating performance in MNCs was nonmonotonous. The highest heating performance was obtained from MNC2, which contain 13% Fe (w/w), implying that interparticle interactions in MNCs can be optimized to achieve high heating performance. In addition, the MNCs exhibited good colloidal stability under physiological conditions and maintained their heating efficiency during 48 h of incubation in cell culture medium. Both in vitro and in vivo studies revealed excellent biocompatibility of the MNC.Conclusion: Our nanocomposites, comprising biocompatible IONPs and PLA, display improved heating efficiency, good colloidal stability, and cytocompatibility, and thus will be beneficial for diverse biomedical applications, including magnetic hyperthermia for cancer treatment.Keywords: iron oxide nanoparticle, hyperthermia, inter-particle interactions, nanomedicine