In order to resolve the wellbore stability of hard-brittle shale of Nanpu oilfield with nano-micro pore throat of shale，nano-micron plugging material HSM and HGW was introduced and the recipe of the micro-nano and anti-sloughing drilling fluid，composed of 3% bentonite muds， 1.2% tackifier DSP-2， 6% filtrate reducer SPNH， 3% filtrate reducer SMP-I， 1% viscosity-reducer SMT，0.5% inhibitor AI-1，0.8% heat stabilizer Na2SO3，1% micron plugging agent FT3000，5% KCl，2% Waterproof lock agent HAR-D，2% nano plugging agent HSM and 3% submicron plugging agent HGW，was determined.Meanwhile，the filtration property，plugging property，and anti-sloughing inhibitive of the obtained drilling fluid was studied. The results showed that the addition of 2%HSM and 3%HGW could increase the membrane efficiency from 0.21 to 0.38，reduce the filter loss by more than 35%，decrease the PPT filtrate loss and initial filtration rate，and delay the pressure transmission. The drilling fluid had favorable filtration property，plugging property，and inhibitive. After being aged at the temperature of 150℃ for 16 h，the API and HTHP filter loss of the drilling fluid was 3.7 mL and 11 mL，respectively；the linear expansion ratio of the bentonite sheeting after being soaked in the drilling fluid for 24 h was only 13.29%，the rolling recovery of mudstone debris in the drilling fluid after aging for 16 h at the temperature of 150℃ was 93.3%. Field application showed that the drilling fluid could improve borehole quality with regular borehole gauge effectively，and the drilling speed was 35.29% higher than that of the adjacent wells. The multiple purposes of well stability，reservoir protection and optimized drilling was achieved.