Spurred by recent advances in materials chemistry, molecular pharmaceutics and nanobiotechnology, stimuli-responsive “smart” systems offer opportunities for precisely delivering drugs in dose-, spatial- and temporal-controlled manners. In this talk, I will discuss our ongoing efforts in developing physiological signal-triggered on-demand drug delivery systems, especially based on artificial cells or engineered cells. I will first present the glucose-responsive synthetic systems for biomimetic delivery of insulin for diabetes treatment. Bio-responsive polymeric microneedle patches will be emphasized. I will further discuss programmable delivery of anticancer therapeutics, the release of which can be activated in the tumor microenvironment or subcellular environment. Our latest study utilizing platelets for targeted delivery of immune checkpoint inhibitors will be specifically introduced.