Massage-Mimicking Nanosheets Mechanically Reorganize Inter-organelle Contacts to Restore Mitochondrial Functions in Parkinson's Disease.

Parkinson's disease (PD) is exacerbated by dysfunction of inter-organelle contact, which depends on cellular responses to the mechanical microenvironment and can be regulated by external mechanical forces. Delivering dynamic mechanical forces to neural cells proves challenging due to the skull. Inspired by the effects of massage; here PEGylated black phosphorus nanosheets (PEG-BPNS), known for their excellent biocompatibility, biodegradability, specific surface area, mechanical strength, and flexibility, are introduced, which are capable of adhering to neural cell membrane and generating mechanical stimulation with their lateral size of 200 nm, exhibiting therapeutic potential in a 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine-induced PD mouse model by regulating inter-organelle contacts. Specifically, it is found that 200 nm PEG-BPNS, acting as "NanoMassage," significantly increase  plasma membrane tension, as evidenced by fluorescent lipid tension reporter fluorescence lifetime analysis. This mechanical force modulates actin reorganization, subsequently regulating the contacts between actin, mitochondria, and endoplasmic reticulum, further controlling mitochondrial fission and mitigating mitochondrial dysfunction in PD, exhibiting therapeutic efficacy via intranasal administration. These findings provide a noninvasive strategy for applying mechanical stimulation to deep brain areas and elucidate the mechanism of NanoMassage mediating inter-organelle contacts, suggesting the rational design of "NanoMassage" to remodel inter-organelle communications in neurodegenerative disease treatment.