In this work, a vehicle based on covalent organic framework (COF)‐coated mesoporous silica nanospheres (MSN) with a sandwiched polyethyleneimine (PEI) layer, is designed as MPCP. The space‐specific drugs‐loaded vehicle (M_GP_PC_LP) is obtained by separately incorporating a chemotherapeutic agent (gemcitabine, G) into the MSN core, a P glycoprotein inhibitor (LY 335979, P) into the PEI layer, and an extracellular matrix disruptor (losartan, L) into the COF shell. Thereafter, a programmed drug delivery is achieved via the ordered degradation from COF shell to MSN core. This MPCP‐based vehicle design suggests a robust space–time conversion strategy to achieve programmed multi‐drugs delivery and represents a new avenue to the treatment of pancreatic carcinoma by overcoming extracellular matrix and drug reflux barriers. This work was mainly accomplished by Ph.D. candidate Taotao Huo.