pH-responsive chitosan–mesoporous organosilica nanoplatform: enhancement of biocompatibility and tumor eradication for precision colorectal cancer chemotherapy

Chemotherapy for colorectal cancer (CRC) is frequently compromised by insufficient tumor selectivity and severe off-target gastrointestinal toxicity. Addressing these limitations, we have engineered a pH-responsive core–shell nanocarrier based on chitosan (CS)-functionalized mesoporous organosilica materials (CS-MOMs). This core-shell nanoplatform utilize a CS coating as a pH-sensitive gatekeeper enabling rapid doxorubicin (DOX) release within the acidic tumor microenvironment and lysosomal compartment (pH 5.4) while preserving structural integrity to prevent premature leakage under physiological conditions (pH 7.2). In colorectal cancer cells, DOX@CS-MOMs exert superior antiproliferative activity to free DOX through acid-triggered intracellular reactive oxygen species accumulation, shifting the Bcl-2/Bax balance toward apoptosis, and activating the Caspase-3 cascade. Crucially, via in vitro intestinal epithelium model, the nanocarrier preserve barrier integrity—maintaining trans-epithelial electrical resistance and tight junction protein expression (ZO-1 and Occludin), and the mucus layer—while mitigating oxidative stress. Confirmed by excellent biocompatibility in vivo, this work establishes a novel nanotherapeutic strategy that combines antitumor effects with active protection of the intestinal mucosa, offering a promising approach to enhance the precision and safety of CRC treatment.