The shale formation of the Longtan Formation in the transitional marine-continental facies in the southern Sichuan Area is prone to wellbore instability during drilling. The hydration of shale exacerbates the propagation of micro-cracks, weakening the support provided by the drilling fluid to the wellbore. The shale from the Longtan Formation in the Zi 205 well area of southern Sichuan was selected as the material for investigation. Pressure transmission tests were conducted to evaluate the performance of the existing drilling fluids, and a “shell-core” nano-plugging agent was optimized through sand pack sealing experiments to systematically assess its inhibition and plugging effects. The results indicate that the Longtan Group formation exhibits well-developed layering, with some small layers being fractured. Wellbore instability is characterized by localized block falls and large-scale collapses. The plugging indices of the existing drilling fluid are 0.259 and 0.264, showing poor performance in plugging nanometer-sized pores and pressure isolation. After the addition of the nano-plugging agent, API(American Petroleum Institute)fluid loss and HTHP (high temperature high pressure) fluid loss of the drilling fluid decreased by 9.7% and 62.0%, respectively. After 36 hours of the pressure transmission experiment, the downstream pressure was 28 kPa, and the pressure isolation efficiency exceeded 98%, achieving highly effective fluid pressure isolation. These findings provide guidance for the practical application of nano-plugging agent in shale formations of Longtan Formation and offer important reference value for the development of such formations.