Tapentadol hydrochloride (TPD) is a novel analgesic with two mechanisms of actions: agonist activity at the l-opioid receptor and norepinephrine reuptake inhibition. The conventional delivery of TPD is problematic, owing to its extensive first pass metabolism, low lipophilicity and short half-life that leads to low bioavailability (32%). The intent of the present work was aimed at bio-fabrication of polysorbate 80 coated chitosan nanoparticles (CS-NPs) for CNS targeting of TPD using factorial design approach for enhanced delivery of drug. TPD-CS-NPs were prepared by ionic gelation technique and optimized using 23 factorial design of experiment. The effect of polymer (CS) and cross linker (TPP) concentration was studied on particle size (PS) and entrapment efficiency (EE %). Formulation CNP6 was considered desirable with optimal EE % (87.1 +/- 0.4%), PS (329.3 +/- 1.0 nm), zeta potential (30.4 +/- 0.7 mV) and cumulative drug release of 73.5 +/- 2.9% in 24 h. Differential scanning calorimetry revealed the absence of any chemical interaction between TPD, CS, and TPP while SEM study confirmed spherical morphology. In vivo pharmacodynamic studies on rat model verified that pure drug was unable to show considerable antinociceptive activity owing to its hydrophilic nature, conversely polysorbate 80 coated TPD-CS-NPs showed a significant antinociceptive effect over a period of 24 h, which is evidence for brain targeting of TPD-CS-NPs. Accelerated stability studies of optimized batch demonstrated a negligible change in the average PS and EE % after storage at 25 +/- 2 degrees C/60 +/- 5% RH (relative humidity) for the period of three months. The ANOVA results for the dependent variables demonstrated that the model was significant (P values < 0.05) for response variables. Above finding suggested practicability of investigated system for effective targeting of many therapeutic agents in the treatment of many life threatening CNS disorders.