Concerted pH‐Responsive Performance of Chitosan–Deoxycholic Acid as a Polymeric Molecular Block for Cancer Cell Disruption

Molecular blocks (MBs) offer a drug-free approach to cancer therapy by utilizing polymeric nanoparticles that remain dispersed in the bloodstream but aggregate within the acidic tumor microenvironment (pH 6.3-6.5) to disrupt cancer cell membranes. Herein, a pH-responsive polymeric MB is developed by conjugating deoxycholic acid (DCA) to chitosan (CS) through a water-based modification using CS succinate (CS-S). The resulting CS-S-DCA nanoparticles exhibit significant aggregation at pH 6.2 while maintaining a smaller size at physiological pH (7.4), demonstrating pH-triggered behavior. This leads to selective cytotoxicity against cancer cell lines (MiaPaCa-2, A-549, and HT-29) while preserving compatibility with normal human dermal fibroblasts. Fluorescence imaging confirms preferential adhesion of CS-S-DCA to cancer cells over normal cells. Encouraged by these findings, in vivo studies in a mouse model are conducted, which reveal significant tumor suppression without the use of conventional drugs. This work highlights the potential of concerted pH-responsive polymeric MBs as a promising and biocompatible strategy for drug-free cancer therapy.