The Relationship between In Vivo Toxicity and Responsive pH in Transistor‐Like pH‐Sensitive Nanodetergents

Subacidity-responsive materials (saRMs) have attracted considerable attention for disease-specific pH-responsive imaging and therapy. However, the guidance for their pH-responsive design, aimed at achieving effective responses at lesion sites while minimizing unwanted responses in normal tissues, is inadequate and challenged by the subtle pH difference between the desired responsive pH and the pH of normal tissues. Here, the correlation between the responsive pH of 'proton transistor' nanodetergents (pTNTs) is investigated and the in vivo toxicity caused by unwanted responses in normal tissues, taking advantage of their refined responsive pH and the easily characterized membranolytic activity and cytotoxicity following response. It is designed and selected five pTNTs that undergo a refined transition from an inactive "OFF" state with sealed membranolytic activity and cytotoxicity to an active "ON" state with potent membranolytic activity and cytotoxicity within a 0.1 pH perturbation at transition pH (pH_t) values of 7.2, 7.1, 6.9, 6.8, and 6.7, respectively. A significant correlation between the in vivo toxicity of these pTNTs and their pH_t for membranolytic activity is observed. And non-negligible changes in the organ toxicity of pTNTs are induced by every 0.1 or 0.2 pH shift of pH_t. After intravenous administration, pTNTs with a pH_t value of 7.2 or 7.1 induced significant hepatotoxicity and cardiotoxicity, while no significant toxicity is detected for pTNTs with pH_t values ranging from 6.8 to 6.7. This hepatoxicity is found to be associated with the tissue's pH environment-dependent activation of membranolytic activity. This study can provide guidance for designing pH-responsive membranolytic materials and saRMs to minimize their toxicity and unwanted response in normal tissues.