Exposure to cigarette smoke (CS) is a major risk of developing serious diseases such as lung cancer, COPD or cardiovascular disease. The development of new tobacco products that could reduce such health impact is ongoing and requires a careful safety assessment strategy. To investigate the effect of the aerosol generated by Philip Morris International’s candidate Modified Risk Tobacco Product (MRTP), named Tobacco Heating System 2.2 (THS2.2), an in vitro model mimicking the human nasal epithelium was exposed for 28 min at the air-liquid interface to various doses. In parallel, exposure to fresh air (sham control) or to mainstream smoke from conventional cigarette (at doses where nicotine level within the aerosol are matching those of THS2.2 product) was performed. Various endpoints (cytotoxicity, CYP1A1/1B1 enzyme activity, inflammatory mediators release, morphological and transcriptomic changes) were collected at different times following exposure (4, 24, 48 and 72h) to identify and compare the dose- and time-dependent effect of each exposure conditions. By using systems toxicology-based risk assessment approaches combining computable biological network models and gene expression changes, we compared the molecular perturbations in both conventional combustible cigarettes and MRTP exposure conditions. While significant effect was quantified over different post-exposure time points in the networks representing cell death, inflammation, proliferation and cellular stress after CS exposure, the impact of THS2.2 exposure (at similar nicotine dose) was closer to sham controls and mostly limited at the earliest time point (4h). The results of all the additional endpoints measured during this study support a reduced impact of THS2.2 exposure on the nasal epithelial tissue culture compared to conventional CS. In conclusion, the side-by-side evaluation of the biological impact of comparable doses of THS2.2 aerosol and conventional CS shows a reduced exposure effect of this new tobacco product on human nasal epithelial tissue culture.