Coaxial electrostatic spray technology has received extensive attention in fabricating micro/nanoparticles for drug delivery. However, there are few reports on applying this technology in preparing albumin nanoparticles. In this study, the bufalin (BF) and nintedanib (NDNB) co-loaded ursodeoxycholic acid and p-biguanides benzoic acid decorated albumin sub-microparticles (BN-DUB subMPs) were fabricated by coaxial electrostatic spray technology and optimized by central composite design. Five percent of albumin (contained 0.7% polyethylene oxide) solution was selected as the shell solution which ejected through outer axis with the flow rate of 0.07 mm/min, while the core solution which contained by BF and NDNB ethanol solution was ejected through inner axis with the flow rate of 0.05 mm/min. In vitro cell studies revealed that the modified albumin possessed good biocompatibility. What's more, the BN-DUB subMPs enhanced the inhibitory effect on the growth of LLC cells efficiently. The pharmacokinetics study showed that the t and AUC of BN-DUB subMPs increased significantly compared with that of the drug solution, which indicated the improved in vivo stability of modified albumin nanoparticles. Thus, this study provided a novel and simple technical platform for the development of albumin-based drug carriers.