Flexible substrates are essential for flexible sensors, providing support and flexibility while impacting sensor stability. Inspired by the nacre microstructure, a novel flexible substrate was developed in this study called PPSN (paper/PDMS/Si3N4 nanoparticles) substrate. Comprising three materials that mimic the functions of “bricks,” “mortar,” and “proteins” in the nacre structure, PPSN offers the advantages such as cost-effectiveness, high temperature resistance, deformation resistance, and stable thermomechanical properties. Experimental results demonstrate that PPSN effectively overcomes the limitations of paper and PDMS, providing efficient interface coupling and fatigue durability, withstanding over 10,000 bending cycles. Additionally, the increased surface area facilitates material printing. Analyzing the impact of varying Si3N4 content on substrate performance reveals that 1.0 wt% Si3N4 content yields the optimal elastic modulus, while at 3.0 wt% Si3N4 content, hydrophobicity reaches its maximum. Moreover, the evaluation of thermal performance indicates that, despite transient thermal decomposition, PPSN substrate remains stable even at high temperatures. This is attributed to interactions between materials, interfacial bridging, and heterogeneous arrangement, ensuring the stability of both mechanical and thermal properties. Most importantly, this study introduces innovative possibilities for low-cost biomimetic processes and improved flexible substrate performance, offering significant scientific and practical value.