A simple, label-free and cost effective sensor have been studied for reliable urea/glucose sensing, and common serum analyte detection comparable with market available urea "Assay Kit" is also performed by using SiO 2 and CdSe-ZnS nanoparticles in electrolyte-insulator-semiconductor structure for the first time. Thermally grown SiO 2 membrane has shown lower pH detection limit (0.081) and lowest drift rate (2.9 mV/hr) than those of the sputtering and E-beam deposited SiO 2 membranes. The urea detection at physiological buffer pH 7.4 with sensitivity of ∼1.6 mV/mg.dl −1 at linear range of 6 to 36 mg/dl is shown. The pH detection limit is further reduced (0.074) by using chaperonin protein mediated CdSe-ZnS nanoparticles assembly over SiO 2 surface owing to high pH sensitivity of 55 mV/pH. The sensing mechanism is due to the SiO x content decreased with increasing pH value. This suggests the lower H + ions absorption on the sensing membrane surface, which is observed by X-ray photo-electron spectroscopy. The glucose concentration is detected by using the core-shell CdSe-ZnS nanoparticles through H 2 O 2 sensing because of reduction/oxidation (redox) properties of Zn as well as Zn 2+ ions generation. Due to the high catalytic activity for H 2 O 2 sensitivity, low detection limit of 1 μM is obtained, which will help to detect glucose using this bio-chip in future. The surface charge as well as potential variation of sensing membranes corresponds to ionic concentration can be used for detection of bio-molecules. [3][4][5] Basically, the pH as well as ionic concentration change (H + and OH − ) is major product of enzymatic reaction with analytes (urea, creatinine, acetylcholine, tributyrine, glucose, etc. 6-8 ), which can be measured by using electrolyte-insulator-semiconductor (EIS) structures. Among those analytes, urea and glucose are the very common potential biomarkers for diagnosis of common diseases such as heart failure, diabetes, and kidney injury. [9][10][11][12] Generally, the urea concentration has been detected through pH change. 13,14 They have reported the detection of glucose concentration by measuring the resultant pH change in presence of glucose oxidase. However, small change of pH restricts the glucose measurement at lower concentration and encourages to sense other catalysis product. Hydrogen-peroxide (H 2 O 2 ) is also a catalysis product of selective enzymatic degradation of glucose, cholesterol, lactate, and so on. [15][16][17] In this regards, the sensing membrane in EIS structure has a key role to detect pH or H 2 O 2 for easy use in our daily life with low cost. Consequently, many materials such as SiO 2 , Si 3 N 4 , Al 2 O 3 , HfO 2 , and Ta 2 O 5 have been investigated for pH sensing.18-21 Hal et al. 22 have reported the high intrinsic buffer capacity of SiO 2 at low concentrated basic pH buffer results into higher surface sites and membrane-electrolyte interface reactivity. Due to very simple structure and good interface with substrate, SiO 2 is a reliable membrane to develop urea senso...