In-situ activation of CuAl-LDH nanosheets to catalyze bioorthogonal chemistry in vivo in tumor microenvironment for precise chemotherapy and chemodynamic therapy

Precise activation of therapeutic molecules in tumor tissues is the key step to ensure targeted antitumor performance and reduce adverse effects towards normal tissues and organs. Although the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), i.e., bioorthogonal chemistry, has been used for the rapid synthesis of anticancer drugs in cells, it remains a great challenge to realize precise in vivo drug synthesis in tumor sites for precise cancer treatment. In this work, we first report the in-situ activation of CuAl-layered double hydroxide (CuAl-LDH) nanosheets to realize Cu(I)-catalyzed bioorthogonal chemistry in vivo in tumor microenvironment (TME) for precise chemotherapy and chemodynamic therapy (CDT). The Cu(II) ions in the biocompatible CuAl-LDH nanosheets can be in-situ reduced to Cu(I) ions partially by the overexpressed glutathione in TME. The generated Cu(I) can serve as a catalyst to catalyze the CuAAC reaction between alkyne and azide in TME, thus realizing in vivo drug synthesis for precise chemotherapy. Meanwhile, the generated Cu(I) can catalyze the Fenton-like reaction to generate toxic hydroxyl radicals (⋅OH) from H2O2 in TME for CDT. Therefore, CuAl-LDHs can be used for the targeted synergistic chemotherapy and CDT to achieve highly precise and efficient elimination of cancer cells in vitro and inhibition of tumors in vivo.