Smart biocompatible materials, responsive to various external stimuli, hold immense potential in the development of biosensors for low-cost diagnostics. The present paper outlines the development of smart enzyme-responsive core-shell nanoparticle-based sensors as low-cost diagnostics for alpha amylase detection. The biocompatible core-shell nanoparticles of 200–250 nm size consisted of a chitosan-tripolyphosphate core formed by ionic gelation coated with a starch-iodine shell. In the presence of specific concentrations of amylase, the starch-iodine shell was disrupted and resulted in the exposure of core. This application herein describes a visible switch in color from blue to red towards the point-of-care detection of salivary alpha amylase (sAA). Stress and other autonomic disturbances can be diagnosed by measuring this biomarker. Also, alpha amylase can be used in the detection of latent saliva at crime scenes for forensic investigations. Using the present platform technology, a paper-based diagnostic was developed for detection of salivary alpha amylase that demonstrated a limit of detection (LoD) of 140 units/ml (70 mg/ml) at 5 minutes while a coated swab developed from the nanoparticles for crime scene investigations could achieve an LoD of 2.5 units/ml (1.25 mg/ml) over 30 minutes. The nanoparticles demonstrated stability and reproducibility with no interference seen with other substances in saliva. The present paper provides a proof-of-concept technology underscoring the utility of smart nanoparticles in affordable, versatile biosensing platforms like paper-based and swab-based formats for such diverse applications as diagnostics for stress and in forensics.