Rui Fang,1,2 Shupei Qiao,1 Yi Liu,1 Qingyuan Meng,3 Xiongbiao Chen,2,4 Bing Song,5 Xiaolu Hou,6 Weiming Tian1 1Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin, People’s Republic of China; 2Division of Biomedical Engineering, University of Saskatchewan, Saskatoon, SK, Canada; 3State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, People’s Republic of China; 4Department of Mechanical Engineering, University of Saskatchewan, Saskatoon, SK, Canada; 5College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 6Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China Abstract: Dedifferentiation and proliferation of endogenous cardiomyocytes in situ can effectively improve cardiac repair following myocardial infarction (MI). 6-Bromoindirubin-3-oxime (BIO) and insulin-like growth factor 1 (IGF-1) are two potent factors that promote cardiomyocyte survival and proliferation. However, their delivery for sustained release in MI-affected areas has proved to be challenging. In the current research, we present a study on the sustained co-delivery of BIO and IGF-1 in a hybrid hydrogel system to simulate endogenous cardiac repair in an MI rat model. Both BIO and IGF-1 were efficiently encapsulated in gelatin nanoparticles, which were later cross-linked with the oxidized alginate to form a novel hybrid hydrogel system. The in vivo results indicated that the hybrid system could enhance the proliferation of cardiomyocytes in situ and could promote revascularization around the MI sites, allowing improved cardiac function. Taken together, we concluded that the hybrid hydrogel system can co-deliver BIO and IGF-1 to areas of MI and thus improve cardiac function by promoting the proliferation of cardiomyocytes and revascularization. Keywords: myocardial infarction, gelatin nanoparticle, cardiomyocyte proliferation, injectable hydrogel