This research uses a Quality-by-Design (QbD) methodology to design and optimize a thermoresponsive in-situ nasal gel drug delivery system; the gel includes nanosized antiviral drugs with the goal of enhancing viral respiratory infections local drug delivery. Poloxamer 407, Poloxamer 188 and Hydroxypropyl Methylcellulose (HPMC), critical formulation variables are systematically examined using a Box-Behnken design as a part of Response Surface Methodology (RSM) to determine their effects on critical quality attributes (CQAs) such as the gelation temperature, viscosity and release of the drug. The streamlined formulation exhibits a gelation temperature in the physiological range, adequate viscosity to deliver drugs through the nose, and lasts over 12 hours. In Wistar rat testing in vivo, nasal retention is superior, adhesion on the mucosal surface is improved, and therapeutic effect is better than with conventional drug solutions. The ANOVA statistical analysis shows that the factors of formulation have a significant effect on the result (p 0.95) is significant which proves the predictive power and strength of the QbD model. These findings provide positive evidence that confirms the presence of a therapeutic window of the optimized thermoresponsive nasal gel as a translational clinical intervention of optimized antiviral therapy and that the QbD concepts can be used systematically and consistently guide the design and development of formulations.