pH/GSH-Driven inside-out nanoreactor initiating copper(I)-precursor chelation-promoted bioorthogonal therapy

The click chemistry catalyzed by transition metals is the research front line for bioorthogonal therapeutics. However, it demands the use of external ligands to form transition metal–ligand complexes for the catalytic enhancement, thus leading to biosafety concerns on the undesired side effects of the complexes or the additional ligands themselves during therapies. Here we report a pH/GSH-driven inside-out nanoreactor initiating Cu(I)-precursor chelation-promoted bioorthogonal catalysis against malignant tumors. It comparts the precursors (Azide and Alkyne) and Cu(II) safely with disulfide-functionalized hyaluronic acid-polycarprolactone (abbr. PCHP1) polymersome structure. Once sensing the pH/GSH changes typically in tumor microenvironment, our nanoreactor starts with a unique programed releasing, allowing for the inside-out translocation of Azide with the highest priority. Subsequently the Cu(I)-Azide chelation can promote the catalytic reaction to generate drug molecules in a highly efficient, ligand-free manner. The PCHP1 nanoreactor can suppress malignant tumors significantly better than the other control groups in the in vitro and in vivo experiments, while inducing minimal side effects. Our strategy of ligand-free Cu(I)-precursor chelation promoted click chemistry will facilitate the development of bioorthogonal catalytic therapies for clinical translation.