Ultrasound-Triggered\nNanogel Boosts Chemotherapy and\nImmunomodulation in Colorectal Cancer

Chemotherapy is the\nprimary therapy for colorectal cancer.\nHowever,\nits efficacy has been limited by chemoresistance, which is mainly\ncaused by inadequate intratumoral drug accumulation and immunosuppressive\nmicroenvironments. To address these limitations, we developed a low-intensity\nultrasound (LIU)-controlled and charge-reversible nanogel (R-NG),\nutilizing conjugated chitosan-polypyrrole polymers linked via thioketal\nbonds, with TiO<sub>2</sub> absorbed onto its surface. Following the\nloading of oxaliplatin, the Oxa-R-NGs were ultimately synthesized.\nIn the acidic tumor environment, the protonation of the pyrrole ring\ntriggered the conversion of Oxa-R-NG into a positively charged form,\nthereby enhancing tumor penetration and cellular internalization.\nBased on the charge conversion, intratumoral accumulating Oxa-R-NG\nwas triggered by LIU to continuously generate reactive oxygen species\n(ROS), which not only disrupted thioketal bonds to liberate oxaliplatin\nbut also regulated tumor-associated macrophage polarization. Consequently,\nOxa-R-NG boosted the chemotherapy for colorectal cancer by improving\nintratumoral drug accumulation and reversing the local immunosuppressive\nmicroenvironment synergistically.