CuNCs-Based pH-Responsive Degradable Nanoplatform for Enhanced CDT/IIT Synergistic Tumor Therapy in a “One-Stone-Two-Birds” Manner

Tumor-associated macrophages (TAMs) account for 30%–50% of tumor tissue and are involved in tumorigenesis, progression, invasion, and metastasis. Thus, tumor cells are no longer the only target for tumor therapy. Here, we proposed a strategy of "one-stone-two-birds" by targeting tumor cells and M2 TAMs simultaneously with ion interference therapy (IIT) synergistic chemodynamic therapy (CDT) via a nanoplatform (CZPM). The CZPM nanoplatform was prepared by employing CuNCs as a source of light and Fenton metal, encapsulated with ZIF-8 for synergistic IIT, and finally modified with mannose. The obtained CZPM nanoplatform could enhance cellular uptake of CT26 and M2 TAMs and respond to cleavage in the acidic environment of endosomes and lysosomes, releasing Zn2+ and CuNCs for IIT synergistically enhancing CDT. In vitro and in vivo experiments confirmed that the CZPM showed significant therapeutic effects. In conclusion, an effective dual-targeting and dual-therapeutic strategy has been developed based on the CZPM nanoplatform.