Dual pH/temperature-responsive cellulose nanocrystals with tailored dual-triggered structural adaptability for controlled-release oral tablet.

Designing oral solid preparations with responsive release mechanisms is crucial for achieving precise therapeutic efficacy in gastrointestinal diseases. In this work, a dual pH/temperature-responsive cellulose nanocrystal (CNCs-D-N) was engineered by grafting a stimuli-sensitive copolymer onto carboxylated cellulose nanocrystal, thereby endowing tailored dual-triggered structural adaptability. The CNCs-D-N exhibited pH-dependent protonation-deprotonation equilibria and thermally induced chain conformational transitions, which cooperatively regulated molecular extension and contraction, enabling rapid and controllable drug release. Tetracycline hydrochloride was subsequently wet-loaded into CNCs-D-N to fabricate stimuli-sensitive tablets (CNC@DNWT), which showed excellent mechanical robustness (hardness: 32.64 N; brittleness: 0.31%), high drug loading capacity (99%), and ultrafast release initiation (7 s). Importantly, CNC@DNWT achieved a cumulative release of 99% under simulated gastric conditions (pH = 3, 37 °C), underscoring synergistic role of dual stimuli in tuning release kinetics. By bridging molecular-level adaptability with macroscopic delivery performance, this study provides a mechanistic strategy for the development of intelligent cellulose-based oral formulations with promising potential for targeted gastric cancer therapy.