Specific accumulation of therapeutics at tumor sites to improve in vivo biodistribution and therapeutic efficacy of anticancer drugs is a major challenge for cancer therapy. Herein, we demonstrate a new generation of intelligent nanosystem integrating multiple functionalities in a single carrier based on multifunctional multiblock polyurethane (MMPU). The smart nanocarriers equipped with stealth, active targeting, and internalizable properties can ferry paclitaxel selectively into tumor tissue, rapidly enter cancer cells, and controllably release their payload in response to an intracellular acidic environment, thus resulting in an improved biodistribution and excellent antitumor activity in vivo. Our work provides a facile and versatile approach for the design and fabrication of smart intracellular targeted nanovehicles for effective cancer treatment, and opens a new era in the development of biodegradable polyurethanes for next-generation nanodelivery systems.