Engineering pH-responsive mesoporous silica nanocarriers through maleated chitosan gating for controlled doxorubicin release

Premature drug leakage and low tumor specificity remain major barriers to effective chemotherapy. This study aims to develop a pH-responsive mesoporous silica nanoparticle (MSN) platform with engineered interfacial design to enhance doxorubicin (DOX) delivery for cervical cancer therapy. The research question was whether covalent conjugation of maleated chitosan to aminated MSNs could provide stable pore gating, trigger-controlled release in acidic tumor microenvironments, and improve therapeutic efficacy.MSNs were synthesized and functionalized with 3-aminopropyltriethoxysilane (APTES) before covalent conjugation with maleated chitosan (ChiMA). Comprehensive chemical, morphological, and structural analyses confirmed successful surface modification and preserved mesostructure. Doxorubicin (DOX) loading and pH-dependent release were evaluated, and kinetic modeling was performed to determine the release mechanism. In vitro cytotoxicity study was conducted using HeLa cells. MSN-Chi nanocarriers retained spherical morphology and uniform mesoporosity post-functionalization. This MSN-Chi was used to load DOX, having drug loading capacity (DLC) and encapsulation efficiency (EE) about 8.94 ± 0.36 wt% and 89.41 ± 3.63%, respectively. DOX release was pH-sensitive, showing rapid release at pH 5.0 and sustained retention at pH 7.4, consistent with a diffusion-controlled mechanism. DOX@MSN-Chi demonstrated significantly greater cytotoxicity (IC 50 ≈ 4 µg/mL) than free DOX (≈ 8 µg/mL), attributed to improved uptake and localized intracellular release. Covalent chitosan gating via maleic anhydride linker offers a robust strategy to control MSN drug release and enhance anticancer potency. This interfacial design transforms conventional chemotherapeutics into tumor-selective nanomedicines, providing a broadly adaptable approach for responsive and safer cancer treatments.