Size Changeable Nanomedicines Assembled by Noncovalent Interactions of Responsive Small Molecules for Enhancing Tumor Therapy

The size of nanocarriers strongly affects their performance in biological systems, especially the capacity to overcome various barriers before delivering the payloads to destinations. However, the optimum size varies at different delivery stages in cancer therapy due to the complicated tumor microenvironment. Relatively large particles are favored for long-term circulation in vivo, while smaller particles contribute to deep penetration into tumor tissues. This dilemma in the size of particles stimulates the development of stimuli-responsive size-shrinking nanocarriers. Herein, we report a facile strategy to construct a tumor-triggered tannic acid (TA) nanoassembly with improved drug delivery efficiency. Cystamine (CA), a small molecule with a disulfide bond, is thus used to mediate TA assembling via cooperative noncovalent interactions, which endows the nanoassembly with intrinsic pH/GSH dual-responsiveness. The obtained TA nanoassemblies were systematically investigated. DOX encapsulated nanoassembly labeled TCFD NP shows high drug loading efficiency, pH/GSH-responsiveness and significant size shrinkage from 122 to 10 nm with simultaneous drug release. The in vitro and in vivo experimental results demonstrate the excellent biocompatibility, sufficient intracellular delivery, enhanced tumor retention/penetration, and superior anticancer efficacy of the small-molecule-mediated nanoassembly. This noncovalent strategy provides a simple method to fabricate a tumor-triggered size-changeable delivery platform to overcome biological barriers.