Environment-responsive charge-inversion polymers enable stable and pH-activatable ternary TiO₂ nanocomplexes

Polymer-inorganic hybrid nanomaterials represent promising platforms for ultrasound-based noninvasive therapy because they combine colloidal stability with environment-responsive activation. This report describes ternary TiO₂ nanocomplexes (NCs) engineered with a rationally designed charge-inversion polymer that can cleave amide bonds at physiological temperature and weakly acidic pH. Introduction of a cyclohexene-based dicarboxylic anhydride in polyallylamine (PAA) endows the resulting polymers with efficient pH-triggered charge inversion within the endosomal pH range, enabling activation under biologically relevant conditions. Coating binary TiO₂-PAA complexes with these polymers produces stable ternary NCs that maintain a negative surface charge at pH 7.4 but shift to a positive surface charge under acidic conditions. The prepared NCs can be internalized by HeLa cells and demonstrate time-dependent endosomal escape, confirming that intracellular charge inversion remains operative in the assembled state. Notably, the polymer coating markedly improves the biocompatibility relative to cationic binary NCs. However, ultrasonic irradiation after endosomal escape induces substantial cytotoxicity, which could be attributed to reactive oxygen species (e.g., singlet oxygen; ¹O₂) generated by TiO₂ nanoparticles in the cytosol. These findings establish a materials-engineering strategy for achieving both extracellular stability and intracellular activation, both of which are critical parameters for designing next-generation ultrasound-responsive biomaterials.