Near-infrared photocatalytic oral microalgae-carbon nitride-based nanozyme ameliorate Parkinson's disease via suppressing gut microbiota-indole-3-lactic acid-brain axis-mediated neuroinflammation

Gut microbiota modulates gut-brain crosstalk in Parkinson's disease (PD), yet effective therapies are still lacking. Herein, we report an orally administrable microalgae-nanozyme platform (SP@SKCN) via combining sulfur/potassium (S/K) co-doped carbon nitride (SKCN) with Spirulina platensis (SP), offering a novel therapeutic strategy for PD. Uniform S-K co-doping significantly narrows the bandgap of carbon nitride (2.2 eV), endowing SKCN with high near-infrared (NIR)-photocatalytic activity and a star-shaped network morphology, realizing NIR-driven water splitting for H2/O2 generation. Meanwhile, SKCN exhibits superoxide dismutase (SOD)/catalase (CAT) mimetic enzyme activities, efficiently scavenging reactive oxygen species (ROS) and synergistically alleviating inflammation. SP incorporation protects SP@SKCN from gastric acid degradation, prolongs its intestinal retention time, and mediates sustained SKCN release. Notably, SP@SKCN remarkedly improves motor deficits, gastrointestinal dysfunctions, and dopaminergic neuron loss in PD mice. 16 S rRNA sequencing and targeted metabolomics reveal that SP@SKCN treatment reverses both PD-associated microbiota changes and the MPTP-induced reduction in indole-3-lactic acid (ILA). Further experiments indicate that SP@SKCN alleviate intestinal inflammation and gut barrier disruption, consequently attenuating systemic inflammation. Mechanistically, SP@SKCN restore the ILA/aryl hydrocarbon receptor (AHR)/NF-κB signaling caused by disturbed gut microbiota mediated the glial cells activation, which eventually reduce dopaminergic neuron death. Collectively, SP@SKCN ameliorates PD via regulating the microbiota-ILA-brain axis.