Nasal microenvironment self-responsive herbal hydrogel alleviates Parkinsonian pathology via the inhibition of α-synuclein liquid-liquid phase separation.

The liquid-liquid phase separation (LLPS) of α-synuclein (α-syn) is recognized as a critical driver of Parkinson's disease (PD) progression. Therefore, inhibiting α-syn LLPS may confer anti-Parkinsonian therapy. Although some small-molecule inhibitors effectively suppress α-syn LLPS, their limited delivery across the blood-brain barrier (BBB) hinders their application. In this study, the natural product baicalein (BA) was found to inhibit α-syn LLPS, and a BA-loaded nasal hydrogel was developed for PD therapy. To avoid the rapid clearance of BA within the nasal cavity, BA was formulated onto the skeleton of carboxymethyl chitosan and 4-formylphenylboronic acid through dynamic intermolecular self-assembly to produce a mucoadhesive hydrogel (CAB2). CAB2 exhibited self-responsive drug release in the weakly acidic and reactive oxygen species-rich microenvironment of the nasal cavity, allowing BA to bypass the BBB and efficiently accumulate in the brain. CAB2 retained the ability of BA to inhibit α-syn LLPS and possessed favorable neuroprotective and anti-neuroinflammatory effects. The therapeutic efficacy of CAB2 extended beyond α-syn LLPS suppression, such that CAB2 also restored autophagic flux, ameliorated oxidative damage, and attenuated neuroinflammatory responses, thus comprehensively remodeling the PD-associated pathological microenvironment. Therefore, this herbal hydrogel capable of self-responsive release in the nasal microenvironment offers a novel therapeutic option for PD.