Contents lists available at ScienceDirectBiomaterialsjournal homepage: www.elsevier.com/locate/biomaterialsExosome-mimetics as an engineered gene-activated matrix induces in-situvascularized osteogenesisYao Zha a,b,1 , Tianyi Lin c,1 , Yawu Li a,b , Xin Zhang a,b , Zihao Wang a,b , Zubing Li c , Yongqin Ye d ,Bin Wang d,∗∗∗ , Shengmin Zhang a,b,∗∗ , Jianglin Wang a,b,∗a Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan, 430074, Chinab Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, Chinac State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospitalof Stomatology, Wuhan University Stomatological Hospital, Wuhan University, Wuhan, 430079, Chinad Department of General Surgery, Shenzhen Children's Hospital, Shenzhen, 518038, ChinaA R T I C L E I N F OKeywords:Exosome-mimeticsCore-shell nanof i berGene-activated matrixAngiogenesisOsteogenesisA B S T R A C TExosome has been considered as an instructive supplement between complicated cell therapy and single gene/protein drug treatment in the f i eld of regenerative medicine due to its excellent biocompatibility, ef f i cientcellular internalization and large loading capacity. Nevertheless, one major issue that extremely restricts thepotential application as gene/drug vehicles is the low yield of nanoscale exosome. Moreover, the intravenousinjection of targeted exosomes may cause the obstruction of blood-rich organs. Thus, herein we fabricated aspecif i c exosome-mimetics (EMs) that could come true mass and fast production exhibited the similar size,morphology and membrane protein markers in comparison with conventional exosomes. To bypass the risk ofintravenous injection and improve the ef f i ciency of topical therapy, we simultaneously applied the engineeredEMs to design a gene-activated matrix (GAM) that could be locally released by encapsulating the plasmid ofvascular endothelial growth factor (VEGF) and f l exibly binding onto a core-shell nanof i ber f i lm. Our f i ndingsshowed that the well-designed engineered EMs-mediated GAM was able to sustainably deliver VEGF gene andsignif i cantly enhance the vascularized osteogenesis in vivo. The current work can not only consolidate theapplied foundation of EMs through the breakthrough of high yield, but also provide a local and ef f ective deliveryof engineered EMs for the in-situ therapy.1. IntroductionExosome as an extracellular nanoscale vesicle with the lipid bilayermembrane plays a pivotal role in cell communication and manipulatesmany biological processes involving cell proliferation, dif f erentiation,tumorigenesis, angiogenesis, and wound healing [1–4]. Recently, exo-some has been verif i ed to exhibit the huge potential in the f i eld of re-generative medicine due to the instructive supplement between ad-vanced cell therapy and conventional drug therapy [5–10]. On the onehand, exosome derives from cells but itself is not a real cell and so it canbypass several issues of traditional cell therapy involving cell source,therapeutic time, immunological risk and medical cost [6,9]. On theother hand, exosome not only contains many genes, proteins andbioactive contents to exhibit similar therapeutic potential comparedwith cell therapy, but also shows a preferable multifunction comparedwith the single protein or gene medicine [10]. Despite exosome em-ploys the aforementioned innate advantages, there still exists severaldrawbacks of low yield, instable ef f i ciency, targeted issue as well asadministration route that extremely af f ect the application of biomole-cular vector [11–13]. Consequently, in this study we apply a novelexosome-mimetics (EMs) with high yield, similar structure and bio-markers in comparison with the routine exosomes to construct an en-gineered gene-activated matrix (GAM) for local therapy.GAM that integrates tissue engineering with gene therapy has re-ceived more and more attentions due to the advantages of local deliveryand expression and high ef f i ciency in topical therapy [14–16].https://doi.org/10.1016/j.biomaterials.2020.119985Received 16 November 2019; Received in revised form 16 March 2020; Accepted 17 March 2020∗ Corresponding author. Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan, 430074, China.∗∗ Corresponding author. Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan, 430074, China.∗∗∗ Corresponding author.E-mail address: jwang520@hust.edu.cn (J. Wang).1 These authors contributed equally to this work.Biomaterials 247 (2020) 119985Available online 27 March 20200142-9612/ © 2020 Elsevier Ltd. All rights reserved.T
