Emulsifier-free poly(methyl methacrylate–styrene) [P(MMA–St)] nanospheres with an average particle size of 100 nm were synthesized in an isopropyl alcohol–water medium by a solvothermal method. Then, through radical graft copolymerization of thermo-sensitive monomer N-isopropylacrylamide (NIPAm) and hydrophilic monomer acrylic acid (AA) onto the surface of P(MMA–St) nanospheres at 80 °C, a series of thermo-sensitive polymer nanospheres, named SD-SEAL with different lower critical solution temperatures (LCST), were prepared by adjusting the mole ratio of NIPAm to AA. The products were characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, thermogravimetric analysis, particle size distribution, and specific surface area analysis. The temperature-sensitive behavior was studied by light transmittance tests, while the sealing performance was investigated by pressure transmission tests with Lungmachi Formation shales. The experimental results showed that the synthesized nanoparticles are sensitive to temperature and had apparent LCST values which increased with an increase in hydrophilic monomer AA. When the temperature was higher than its LCST value, SD-SEAL played a dual role of physical plugging and chemical inhibition, slowed down pressure transmission, and reduced shale permeability remarkably. The plugged layer of shale was changed to being hydrophobic, which greatly improved the shale stability