Rajendra K. Singh ^a,b,c,1, Dong Suk Yoon ^a,d,1, Nandin Mandakhbayar ^a,c,1, Chengji Li ^a,b, Amal George Kurian ^a,b, Na-Hyun Lee ^a,c, Jung-Hwan Lee ^{a,b,c,e,f,g,h}, Hae-Won Kim ^{a,b,c,e,f,g,h,*}

^a Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea ^b Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea ^c Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea ^d Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea ^e Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea ^f Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea ^g Cell & Matter Institute, Dankook University, Cheonan, 31116, Republic of Korea ^h UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea

^* Corresponding author.
¹ These authors equally contributed to this work.

Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-β co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.