Molecular Basis of Cooperativity in pH-Triggered Supramolecular Self-Assembly
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Responsive nanomaterials have become an attractive biosensing platform because of their versatility in varying the size, composition, shape and other physicochemical properties to address the deficiency of conventional sensors such as low sensitivity and specificity. Compared to small molecular sensors, nanoparticle sensors often deploy a multitude of non-covalent interactions (hydrogen bonding, hydrophobic and electrostatic interactions) and the resulting system frequently displays cooperative behaviors. pH is an important physiological parameter that plays a critical role in cellular and tissue homeostasis. Dysregulated pH has been recognized as a universal hallmark of cancer. pH-sensitive nanoparticles have been widely used for tumor imaging, study of endosome/lysosome biology and cancer-targeted drug delivery. Recently, we have established a library of ultra-pH sensitive (UPS) nanoprobes with sharp pH transitions that are finely tunable in a broad range of physiological pH (4-8). The UPS nanoprobes showed significantly improved sensitivity and biological precision over commonly used small molecular and polymeric pH sensors. Here, we performed the mechanistic study of sharp pH response and binary on/off switch, which are absent in common small molecular and polymeric pH sensors or buffers, in pH-triggered supramolecular self-assembly process. Hydrophobic nanophase separation drove cooperative deprotonation of protonated unimers into neutral copolymers inside micelles. This divergent proton distribution characteristic of a representative PDPA copolymers was not observed in commonly used small molecular and polymeric bases (e.g., PEI). The cooperative deprotonation dynamics can explain the significantly decreased pKa and sharpened pH response. Combination of theoretical modeling and experimental validation allowed identification of key structural parameters on impacting pKa and sharpness in pH transition. Inspired by the impact of counter-ions on the self-assembly of UPS block copolymers, we reported a novel specific anion-induced micellization process. In vitro and in vivo experiments suggested an "capture and integration" mechanism underlying the binary tumor margin delineation performance of UPS nanoparticles. Results from this study offer molecular insights to help establish the general principles in nanophase transition and supramolecular self-assembly for the development of new nanomaterials-based sensors with binary on/off switch in chemical and biological sensing.