In this study, we present the development of an innovative dry powder dexamethasone (Dex) nasal delivery system comprising Dex-loaded lipid/alginate nanoparticles incorporated within pectin microspheres (Dex/NPs-loaded pectin microspheres; DNM). DNM microspheres were characterized by the mean diameter of 2.76 ± 0.10 mm, zeta-potential of -36.2 ± 1.1 mV, and drug loading of 3.3 ± 0.3%. The morphology study revealed irregular microsphere surface forming external voids. In contact with simulated nasal fluid, DNM microspheres demonstrated desirable property of moderate swelling and ensured stronger mucoadhesion compared with conventional Dex-loaded pectin microspheres. The strategy of Dex incorporation within the lipid/alginate NPs resulted in prolonged Dex release in relation to Dex being directly entrapped within the conventional pectin microspheres. DNM microspheres showed excellent biocompatibility and rendered Dex permeation across the selected epithelial cell model similar to that of Dex solution. In conclusion, balanced biopharmaceutical properties of the proposed nasal Dex delivery system provides the potential for prolonged contact time with nasal mucosa, prolonged therapeutic effect, and improved patient compliance.