A neurodegenerative disorder, glaucoma is a leading cause of blindness in the world. The conventional treatment strategies do not allow the significant penetration of the drug in the cornea. Therefore, we prepare a brinzolamide (Brz) loaded core-shell nanoparticles (NPs) to enhance the coronial penetration of the drug and thus treating the glaucoma. The shell of the NPs was composed of phosphatidylserine (PS; 1,2-diacyl-sn-glycero-3-phospho-L-serine), whereas the core of the NPs contains the Brz encapsulated in brinzolamide-phosphatidylserine-polymer poly-(DL-lactic acid-co-glycolic acid)-phosphatidylserine (Brz-PS-PLGA). The synthesis of Brz-PS-PLGA was achieved by using a coaxial electrospray process (CEP), which allows the preparation of the particles in a single step. The size of Brz-PS-PLGA with PS shell and brinzolamide-poly (lactic-co-glycolic) acid (Brz-PLGA) without shell was 571 ± 27.02 nm and 456 ± 19.17 nm, respectively. The charges on the surface of Brz-PS-PLGA and Brz-PLGA were (-) 27.45 ± 2.98 mV and (-) 19.47 ± 2.83 mV. The transmission electron microscopy images clearly reveal the PS shell as a light black layer over the dark black PLGA core. The CEP allows the high encapsulation of Brz in Brz-PS-PLGA where percentage of entrapment efficiency for Brz-PS-PLGA was 88.13 ± 6.43%. The release study conducted in a simulated tear fluid revealed the sustained release patterns of Brz from Brz-PS-PLGA and these were nontoxic to the cells as revealed by the cytotoxicity studies. Further, the Brz-PS-PLGA enhanced the coronial penetration of Brz and was capable of significantly reducing the intraocular pressure (IOP) after administration to the rabbit eye in comparison to the Brz-PLGA and free Brz. The results clearly suggest that the PS coating significantly enhances the capability of the particles in reducing IOP.