Gelatin‐Poly(Ethylene Glycol) Functionalized Lipid‐Silica Hybrid Nanostructures With Enhanced Interfacial Properties and Colloidal Stability

ABSTRACT Hybrid nanostructures combining inorganic and lipid components attract interest because their properties can be tailored through surface engineering. However, maintaining structural stability and effective interfacial interactions remains challenging. In this study, liposome‐coated mesoporous silica nanostructures were functionalized with a gelatin‐poly(ethylene glycol)‐folate copolymer to assess the effect of biopolymer coating on lipid‐silica hybrid systems. Spectroscopic, elemental, microscopic, and thermal analyses confirmed multilayer formation and surface functionalization. The optimized particles were near‐spherical, with an average hydrodynamic diameter of approximately 218 nm and a negative surface charge. The gelatin‐based coating improved dispersion stability in serum‐containing media, indicating enhanced colloidal behavior. The optimized formulation showed an encapsulation efficiency of approximately 52.5% and a drug‐loading content of approximately 9.8%. After 72 h, doxorubicin release reached approximately 44.3% at pH 5.5 versus 23% at pH 7.4, demonstrating pH‐responsive behavior. In vitro studies using HeLa cells showed that the blank nanostructures maintained more than 80% cell viability at concentrations up to 200 μg/mL, while the drug‐loaded system exhibited slightly higher cytotoxicity than free doxorubicin. Fluorescence imaging indicated enhanced cellular uptake after surface functionalization. Overall, the gelatin‐based polymer coating enhances the interfacial properties and colloidal stability of lipid‐silica hybrid nanostructures while supporting controlled drug delivery.