Hemocompatibility of Carbosilane Dendrimers as a Therapeutic siRNA Delivery System across Blood–Brain Barrier

The development of nanocarriers offers a promising strategy for the delivery of therapeutics to the central nervous system. However, the clinical translation of nanosystems hinges on their interactions with blood components, which not only dictate their biodistribution and therapeutic efficacy but also may pose potential risks to hemostasis. In this study, we assess the hemocompatibility of a novel, third-generation PEGylated carbosilane dendrimer (G3Si PEG6000) and its dendriplex designed for siRNA delivery across the blood-brain barrier pertinent to Alzheimer's disease. Utilizing a comprehensive array of advanced analytical techniques, we assess cellular responses, cytokine expression, hemorheological properties, hematological parameters, and coagulation dynamics within a physiologically relevant environment. Our findings demonstrate that the investigated nanosystem elicits changes in blood rheology, immune recognition, and the intrinsic coagulation cascade, yet these effects remain below thresholds associated with clinically significant adverse outcomes. Hemolysis was ∼8-fold lower for dendriplexes than the dendrimer in PBS at the highest concentration (accordingly 3.5 ± 0.14% vs 27.46 ± 4.66%, 24 h), in 55% plasma, both formulations were nonhemolytic across all concentrations. Whole blood viscosity increased by up to ∼11% (dendrimer) and ∼16% (dendriplex) relative to the control. At 10 μM, the dendrimer approximately doubled the aPTT, whereas the corresponding dendriplex increased the aPTT by ∼30% of the control. Importantly, neither adverse effects on red blood cell and platelet indices nor toxicological responses in white blood cells were observed under the tested conditions. These findings not only support the translational potential of the studied nanosystem for therapy but also emphasize the critical role of the therapeutic cargo and the formation of a biomolecular corona in shaping the nanocarrier's biological identity and its subsequent interactions within the bloodstream. The results provide a compelling scientific basis for advancing this platform in further investigations.