An acid-seeking carrier-free drug achieves high antitumor activity via a "solution-particle" transition.

Drug nanocarriers that have long been expected to revolutionize cancer therapy have yet to achieve the significant clinical success. Therefore, it remains controversial to pursue a complex drug nanocarrier that lacks clinical relevance. Herein, we developed an easily-synthesized anti-tumor drug that actively seeks the acidic tumor microenvironment while ignoring the normal tissue without the aid of additional carriers. This called "carrier-free" drug (CFD) is capable of switching its morphology from the unstructured solution to the spherical structure in response to tumor acidity. CFDs were the water-soluble zwitterionic unimers to prevent the non-specific distribution in the circulation, whereas they spontaneously formed into the particles tending to accumulation in tumor. CFD overloading in tumor cells caused the lysosomal dysfunction and autophagy blockage, thereby triggered the cell death. All the in vitro and in vivo data demonstrated the tumor-acidity-selective cytotoxicity of CFD. This facile strategy to create a self-delivering anticancer drug may cast a new light on the development of cancer therapy.