Nanoparticle-decorated polymer-coated sub-microbubbles (NP-P-coated SMBs), as proved, have shown promising application prospects in ultrasound imaging, magnetic resonance imaging, drug delivery, and so forth. However, the quantitative evaluation of the stability and GAS mechanical properties of single NP-P-coated SMB is absent. Here, we first reported the stiffness and Young's modulus of single NP-P-coated SMB obtained by the PeakForce mode of atomic force microscopy. Such NP-P-coated SMBs could maintain perfect spherical shapes and have a thinner shell thickness (about 10 nm), as determined by characterization using a transmission electron microscope. Young's modulus of NP-P-coated SMBs is about 4.6 +/- 1.2 GPa, and their stiffness is about 15.0 +/- 3.1 N/m. Both modulus and stiffness are obtained from the linear region in the force-deformation curve and are nearly independent of their sizes. These results should be very useful to evaluate their stability, which plays a key role in maintaining the shell drug loading and acoustic capabilities.