Stealth Protocell System Based on Folated Polyoxyethylene Stearyl Ether-Modified Liposome-Encapsulated Mesoporous Silica for Active Tumor Targeting and pH-Responsive Releasing

Abstract Controlled drug release and enhanced cellular accumulation are critical strategies for improving the efficacy of mesoporous silica nanoparticle (MSN) carriers in cancer therapy. This study describes the development of a hybrid nanocarrier (MLBF) consisting of an MSN core encapsulated within a lipid bilayer modified with folated polyoxyethylene stearyl ether (Brij-FA). This stealth protocell design utilizes Brij-FA to provide a protective steric layer aimed at reducing non-specific clearance while promoting cellular uptake. Physicochemical characterization using Fourier transform infrared, energy-dispersive X-ray spectroscopy, and thermogravimetric analysis confirmed the successful assembly of the LBF shell onto the aminated MSN. The resulting spherical nanoparticles exhibited a hydrodynamic diameter of 191.8 ± 3.2 nm and a zeta potential of −24.4 mV. Using doxorubicin (DOX) as a model cargo, the MLBF system demonstrated distinct pH-responsive release behavior, with significantly higher release rates in simulated tumor microenvironments (pH 5.5) compared to physiological conditions (pH 7.4). In vitro assessments on HeLa cells revealed excellent biocompatibility for the carrier, while DOX-loaded MLBF exhibited potent cytotoxicity comparable to that of the free drug. Confocal microscopy verified superior intracellular internalization of the MLBF system compared to non-folated counterparts, which is likely driven by a combination of favorable physicochemical properties and potential interactions with folate receptors. These findings highlight the potential of the MLBF as a sophisticated platform for targeted and stimuli-responsive cancer treatment.