Folate-Decorated PCL–PEG-Modified Mesoporous Silica Nanoparticles via Disulfide Linkages for Synergistic Triple-Stimuli-Responsive Drug Delivery

The engineering of interfacial architectures and colloidal behavior of nanocarriers dictates the efficacy of targeted drug delivery platforms. In this study, we report a surface modification strategy to functionalize mesoporous silica nanoparticles (MSNs) with a Poly(ε-caprolactone)-Polyethylene glycol-Folic acid (PPF) polymer shell through disulfide (−S-S-) linkages to develop a multistimuli-responsive gatekeeping system (MSN-SS-PPF). Of which, each constituent plays a distinct functional role to achieve multistimuli-responsive capabilities. The disulfide bonds confer reduction sensitivity, the hydrophobic PCL blocks act as enzyme-degradable mesopore gatekeepers, while the PEG segments enhance biocompatibility, and the FA moieties provide active targeting functionality. Physicochemical characterizations confirmed the functionalization steps and clarified the structural properties of the MSN-SS-PPF hybrid nanomaterials. The hydrophobic PCL segments seal the mesopores to prevent premature doxorubicin (DOX) leakage under physiological conditions. The MSN-SS-PPF system exhibits stimuli-responsive drug release behaviors within simulated tumor microenvironments. The acidic pH directly facilitates DOX dissolution via protonation and alters the biochemical interface to enhance the lipase-mediated hydrolytic degradation of the PCL segments. Combined with the redox-triggered cleavage of the surface disulfide linkers, this cooperative mechanism leads to structural disassembly and localized cargo release. Due to folate receptor-mediated endocytosis, the DOX@MSN-SS-PPF nanocarriers increase intracellular accumulation, resulting in enhanced cytotoxicity (IC50 = 0.43 μg/mL) against A549 lung cancer cells compared to free DOX. This work demonstrates a robust surface-engineering strategy to construct copolymer coronas on mesoporous silica cores via disulfide linkages, providing a design framework for advanced, stimuli-responsive hybrid nanoplatforms for drug delivery.