Polysaccharide-mediated in vivo cascade chemistry converts endogenous Cu(II) into copper nanoclusters as super nanozymes for Parkinson's disease treatment.

The causes of Parkinson's disease (PD) so far are controversial, but its chronic nature and epidemiological studies reveal that dyshomeostasis of copper biometals is greatly responsible for the progressive dysfunctions that could fuel a vicious cycle of multiple pathogenic factors throughout PD trajectory. Unfortunately, current medication will exert non-specific removal of copper ions including biologically essential static copper pool in metalloenzyme, further exacerbating the neurotoxic effect associated with copper dyshomeostasis. Here, we reported a cascade neuroprotective therapy, which only utilized polysaccharides (i.e. thymine grafted hyaluronic acid, denoted as TgHA) to transform endogenous neurotoxic Cu(II) ions into red-emissive few-atom copper clusters while leaving the levels of essential biometals unchanged. Moreover, these copper clusters can functionally mimic three main antioxidant enzymes to protect neuronal cells from oxidative damage. In PD mouse model, about 83% of travel distance and 61% of fall latency restored back to normal mice after intraperitoneal injection of TgHA alone, clearly alleviating motor dysfunctions. We envisioned polysaccharide-mediated in vivo cascade chemistry will shift therapeutic paradigm in biometal-involved neurological disorders.