Allergic rhinitis (AR) was a chronic airway inflammatory disease. Nasal administration showed superiorities due to its effective drug absorption. Cetirizine (CTZ) was a common H1-antihistamine in allergic disorders therapy, while hydrophobicity and irritation to nasal mucosa limited its application. In this regard, deoxycholate-chitosan-hydroxybutyl nanoparticles with CTZ covalently grafted and free CTZ encapsulated (CTZ:CDHBCs-NPs) were synthesized as nasal adaptive nano-drug delivery systems. CDHBCs-NPs with various lower critical solution temperature (LCST) (29, 33, 37 °C) were prepared, with particle sizes of ~120 nm and zeta potentials of ~4 mV. In nasal condition (pH 5.5, 33 °C), the diameters of CDHBCs-NPs increased slightly (~129 nm to ~134 nm) because of the pH-responsive expansion. Burst release of free CTZ from CDHBC-29-NPs (~76%) was significantly (p < 0.05) accelerated compared with that of CDHBC-33-NPs and CDHBC-37-NPs (~60%), owing to thermo sensitive drug squeeze out (T > LCST). Incubating with lysozyme (30 μg/mL), CDHBCs-NPs swelled and exhibited ~2-fold increase (p < 0.01) of sizes, with additional CTZ releasing (~5%) attributing to the digestion of polysaccharide backbone covalent connected with CTZ. It could be speculated that stimuli-responsive CDHBCs-NPs might hold tremendous potential as nasal adaptive delivery vehicles in allergic airway inflammatory diseases therapy.