Linagliptin (Lina) is a DPP-4 inhibitor used to treat type II diabetes. However, it has a poor oral bioavailability of 29.5% due to both first-pass effect and P-glycoprotein efflux, offering a significant drawback to its general use. Our research goals were to increase Lina bioavailability and develop an injectable sustained release nanoparticle (NP) formulation with a lower administration frequency to improve patient compliance. All formulations were prepared by single emulsion solvent evaporation technique using poly d,l-lactic-co-glycolic acid (PLGA) as a polymer according to a design of experiment (DoE). The dependent variables were lactide concentration, polymer concentration, and organic phase ratio, while the independent variables were entrapment efficiency, particle size, and in-vitro release after 7 days. In-vivo study on rats through evaluation of pharmacodynamics and pharmacokinetics parameters. The selected formula consisted of a 65:35 lactide concentration, with 150 mg PLGA, and 10 % organic solvent, while TEM of the formula showed a sphere-shaped structure with a smooth surface. Particle size was 541.178 ± 10.4 nm, and entrapment efficiency was 67.134 %, with a long-term sustained release reach of seven days. The pharmacokinetic results showed that AUC 0-∞ increased significantly from 33.73 to 60.53 ng/ml.h, t1/2 was significantly prolonged (231.6 ± 43.9 vs. 11.8 ± 0.3 h), Mean residence time (MRT) was 344.1 ± 61 vs. 3.9 ± 1.5 h, and Vd was 4731 ± 393.7 vs 161.4 ± 87.20 ng/ml, for Lina NPs and oral Lina solutions, respectively (P > 0.05). Pharmacodynamics study of optimized formulation show obvious decrease in blood glucose level in comparison to oral Lina. These findings suggest that the PLGA Lina NPs offer a novel strategy for the development of a once-weekly injectable medicine to help manage blood glucose in individuals who have exhibited the capability to manage type 2