Tuning lipid nanocarrier mechanical properties to improve glioblastoma targeting and blood brain barrier penetration

Nanocarrier lipid systems (NLSs) have emerged as versatile platforms for diagnostic and therapeutic applications, including drug delivery, gene therapy, and vaccine development. Recent advancements highlight their potential in targeting infectious diseases and treating pathological conditions like tumors, largely due to their ability to effectively encapsulate and deliver therapeutic agents. This study focuses on the synthesis and characterization of NLSs with varying lipid compositions to understand their physicochemical and mechanical properties, which are crucial for their performance in biomedical applications. NLSs were prepared using a solvent displacement method, resulting in formulations with different ratios of olive oil and stearic acid. These formulations were characterized to determine their size, polydispersity index, and surface charge. Dynamic Light Scattering and Nanoparticle Tracking Analysis revealed that the size of the NLSs increased with higher stearic acid content. The NLSs demonstrated stability across a range of pH levels and in cell culture medium. The biomolecular corona formation and its impact on surface charge were also evaluated, showing significant effects on NLS stability. Mechanical properties, including rigidity and deformability, were assessed using Atomic Force Microscopy and rheological tests. The study found that increasing stearic acid content enhanced NLS rigidity and adhesion strength, which is crucial for their behaviour in biological systems such as blood circulation, tumor targeting, and cellular uptake. Biological evaluations demonstrated that these mechanical properties significantly influenced bio-interactions. Softer NLSs with a pure olive oil core displayed enhanced translocation across an <i>in vitro</i> blood-brain barrier model, underscoring their potential for drug delivery to the brain. Conversely, glioblastoma cell uptake studies revealed that the more rigid NLSs were internalized more efficiently by U87-MG cells, suggesting a role for stiffness in cellular entry. These findings provide insights into optimizing NLSs for specific therapeutic applications, particularly in overcoming barriers like the blood-brain barrier and targeting cerebral diseases.