Intelligent drug delivery system based on “stimulus-response” mode emerging a promising perspective in next generation lipid-based nanoparticle. Here, we classify signal sources into physical and physiological stimulation according to their origin. The physical signals include temperature, ultrasound, and electromagnetic wave, while physiological signals involve pH, redox condition, and associated proteins. We first summarize external physical response from three main points about efficiency, particle state, and on-demand release. Afterwards, we describe how to design drug delivery using the physiological environment in vivo and present different current application methods. Lastly, we draw a vision of possible future development.