Shell-cross-linking of polymeric micelles by Zn coordination for Photo- and pH dual-sensitive drug delivery

Polymeric micelles is promising candidate for cancer therapy through direct drug delivery to tumor tissues. However, the therapeutic effect of polymeric micelles is limited because of its low critical micelle concentration (CMC) against dilution. Here, we developed a novel shell protection strategy to construct a core-(shell-cross-linking)-corona micelles (CSCCMs) with tunable stability to overcome the restriction of CMC. The unique shell-cross-linking within CSCCMs is designed based on Zn coordination-induced crosslinking mechanism to guarantee efficient drug release. The obtained CSCCMs can be loaded with doxorubicin (DOX) by utilizing the hydrophobic core with photo-responsiveness, while the Zn-cross-linked shell with pH-responsiveness protects the core containing DOX. We demonstrate that the CSCCMs effectively aggregate against dilution to prevent the leakage of drug, while its disassembly is triggered through photo- and pH dual-stimuli, thereby realizing controlled drug delivery at targeted sites. Collectively, the simplicity of our approach, together with the shell protection design derived from Zn coordination-induced shell-crosslinking, demonstrates a robust strategy for the preparation of polymeric micelles with tunable stability, which exhibits potential in improved drug delivery.