Potassium ion-induced complexation of tannic acid and 18-crown-6 enables BSA encapsulation and pH-triggered disassembly

Building on our prior findings that tannic acid (TA) and 18-crown-6 ether (18C6) form well-dispersed complex particles in phosphate buffer containing potassium ions (K), herein we report a novel TA-based complex formed by mixing 3 components: TA, 18C6, and bovine serum albumin (BSA). We first elucidate the complexation mechanism between TA and 18C6 using density functional theory (DFT) calculations and then show that these complexes spontaneously encapsulate FITC-labeled BSA (F-BSA) during their formation in the presence of K. Owing to the high specificity of 18C6 toward K, 18C6 binds to TA at low K concentrations (1.9 mM), while efficient F-BSA encapsulation requires 10 mM K. The resulting ternary complex (TA-18C6-F-BSA) disassembles under acidic conditions (pH ∼5), enabling pH-responsive F-BSA release in the form of TA-F-BSA complexes. While the 18C6 dimer can also encapsulate F-BSA in the presence of K, its stronger intermolecular interactions with TA prevent pH-responsive degradation. However, the dimer shows enhanced thermal stability. These findings highlight the potential of TA-18C6 complexes for protein encapsulation and stimuli-responsive disassembly under physiologically relevant conditions.