The wide use of nanomaterials in medicine and especially in drug delivery had heightened the demand for a safe use of nanoparticles (NPs) before delivered to patients. NPs are used to reduce the toxicity of some drugs; however, the nanocarriers themselves impose risk on the patient health. The creation of NPs safe use guidelines is based on experimental investigation on human cell lines to eliminate the risk of newly synthesized NPs. In this study, toxicity of four novel POSS particles were tested using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and crystal violet assays and exposed for 1,24 and 48h to human skin keratinocytes (HaCaT). Five concentrations investigated ranging between (0.001-100mg/mL) for each particle (size 100nm in diameter). TrisilanolIsooctyl POSS particles significantly reduced the metabolic activity and relative cell number of HaCaTcells lines after 24h exposure. Trisilanol Phenyl, Cyclopentyl and Cyclohexal POSS particles did not show any sign of toxicity; therefore, toxicity may attributed to the shape of the particle. Trisilanol Phenyl, Cyclopentyl and Cyclohexal POSS particles show a promising application in anti-cancer drug delivery.