The application of nanoparticle-based delivery systems is limited by uncontrolled drug release, limited tumor penetration, and poor stability. To solve these problems, a tumor microenvironment pH and enzyme double-responsive shrinkable nanoparticle was developed in this study and defined as LDC (the complex of laponite (LP), doxorubicin (DOX), and chito-oligosaccharides (COS)). LDC has a 100 nm size and contains the anticancer medication DOX, which is stable in serum-containing aqueous solutions and can efficiently accumulate in tumors in vivo. The tumor extracellular matrix is in rich of lysozymes, which can degrade COS and release smaller DOX-containing nanoparticles, making LDC shrink from the initial 100 nm into 30 nm (in diameter) to facilitate the drug to penetrate deeply into the tumor tissue. Furthermore, after being taken up by tumor cells, the acidic and enzymatic cellular microenvironment triggers quick DOX release and rapid killing of cancer cells. LDC exhibits hardly any in vivo toxicity to mice's major organs. These results demonstrated that LDC can ensure a systematically tumor-targeting controlled drug release, deep tumor penetration, and stability in circulation to avoid damages on healthy organs/tissues, demonstrating its potential as an effective thereaputic delivery approach for cancer treatment.