Abstract: The southern block of Weixi'nan Oilfield has abundant low and ultra-low permeability reservoir resources. However, it is located in a complex geological area that is prone to collapse and leakage, making development difficult. In order to reduce costs, improve drilling efficiency and safety, research has been conducted on optimizing drilling design for collapse-prone formations. Based on formation characteristics, the wellbore stability analysis was conducted to optimize the wellbore structure, and the conventional 311.2 mm and 215.9 mm borehole sections were merged into a "two-in-one" 311.2 mm borehole. A nano-scale plugging agent oil-based drilling fluid was developed and applied to enhance plugging and wellbore protection performance. A new type of thorny-tooth PDC bit was designed to improve aggressiveness and adaptability. Combined with trajectory optimization and hydraulic simulation, the well inclination was controlled within 45° to reduce collapse risk. Onsite application shows that the "two-in-one" structure saves 215.9 mm borehole section and the corresponding 177.8 mm liner operation per well, reducing the construction period by approximately 5 days. The rate of penetration (ROP) in the 311.2 mm wellbore increased by 11%～28%. The friction coefficient of the nano drilling fluid is only 0.3, the drilling efficiency reaches 250 m/h, and the wellbore remained stable without falling blocks. Wells TH and SH both achieved production exceeding 100% of the allocated target. This technology system has achieved significant results in the collapse-prone formations in the Weixi'nan Oilfield, providing transferable practical experience for drilling under similar complex conditions.