Abstract: To achieve secured in vivo drug synergy in stroma-rich pancreatic cancer(PDAC) is not an easy task. Ji and Liu et al. demonstrate the rational development of a ratiometrically designed nanocarrier to co-package a CDK4/6 cell cycle inhibitor palbociclib(PAL) plus an autophagy inhibitor hydroxychloroquine(HCQ) for efficient PDAC treatment. The lead formulation was obtained using a computer software aided in vitro screening, followed by a remote drug co-import into a lipid-coated mesoporous silica nanoparticle. The ratiometric nanocarrier led to the synchronized pharmacokinetic(PK) profile and effective intratumoral buildup of the drug pair post intravenous injection, which otherwise exhibited distinctly different biodistribution characteristics. The treatment using PAL/HCQ co-delivery nanoparticles yielded the most effective shrinkage of PDAC in subcutaneous and orthotopic PANC1 mouse models. The mechanistic investigation also demonstrated the activation of anti-apoptosis pathway after repetitive nanoparticle injection in mice, which promoted the authors to introduce a small molecule anti-apoptosis inhibitor to further improve the performance of their already potent nanoparticle in the PDAC mouse model. This work has been published online in Nature Communications on August 25, 2020.