Nanoparticle-based wireless deep brain stimulation system found to reverse Parkinson's disease

ATB NP–mediated photothermal stimulation promotes the activation and depolarization of TRPV1+ cells in vitro. (A and B) An illustration of the design of ATB NPs. (C) Representative FTIR spectra of AuNSs, AT NPs, and ATB NPs. (D) Distribution of ATB NPs (1 × 109/ml) in primary dopaminergic neurons and HEK-293T cells transfected with or without TRPV1 plasmid, as shown by TEM. (E) Working model of ATB NP–mediated photothermal stimulation activating TRPV1 and Ca2+ influx in cells, as determined by Fluo-4 AM probe. (F) Representative Ca2+ influx of control, PFF neurons, and PFF neurons treated with ATB NPs (1 × 109/ml) for 24 hours, before and after NIR laser irradiation (2 W, 20 ms per pulse, 20 Hz) for 1 min. Scale bars, 80 μm. (G) Ca2+ influx of HEK-293T cells transfected with TRPV1 plasmid or empty vector (set as control) incubated with ATB NPs, before and after NIR laser irradiation. Scale bars, 80 μm. (H) Whole-cell patch-clamp traces of TRPV1+ or TRPV1− cells in the presence or absence of ATB NPs for 24 hours and NIR laser treatment for 1 min (n = 5, five replicates). (I) Action potentials in PFF-treated DA neurons in response to ATB NPs and NIR laser irradiation (n = 6, six replicates). (J) Representative immunofluorescence images of c-fos in primary dopaminergic neurons treated with PFF (2 μg/ml) for 3 days, followed by ATB NPs incubation for 24 hours and NIR laser irradiation for 1 min. Scale bars, 80 μm. The data are expressed as the means ± SD. Statistical significance was tested using a two-tailed t test and one-way analysis of variance (ANOVA) analysis. ***P < 0.001 and ****P < 0.0001. (A), (B), and (E) created using BioRender.com. @ CAS / Science Advances

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, primarily characterized by motor dysfunction. Its pathological hallmark is the abnormal aggregation of α-synuclein (α-syn) into insoluble fibrils and Lewy bodies, leading to the degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain. To ameliorate motor symptoms in patients, a common clinical approach, deep brain stimulation (DBS), involves the implantation of electrodes into specific brain regions to modulate neuronal activity through direct electrical stimulation.

Although DBS enhances the efficiency of neuronal regulation, its invasive nature can lead to cognitive decline and emotional disturbances such as depression and anxiety. Subsequently developed non-invasive techniques such as transcranial direct current stimulation and transcranial magnetic stimulation can enhance cortical excitability but are limited by insufficient penetration depth and spatial resolution. Therefore, to develop non-invasive DBS technologies that combine high spatial resolution with strong penetration capabilities is crucial.

In a study published in Science Advances, a research team led by Prof. CHEN Chunying from the National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences designed a wireless photothermal DBS nanosystem, Au@TRPV1@β-syn nanoparticles (ATB NPs). This system achieves precise modulation of degenerated neurons by directly stimulating the endogenous expression of the thermosensitive TRPV1 receptor in neurons, thereby offering new insights into the treatment of PD and other neurodegenerative disorders.

This system consists of three core modules: a photothermal conversion module (gold nanoshells, i.e., AuNSs) for activating the thermosensitive TRPV1 ion channels; a targeting module (TRPV1 antibody) to specifically target dopaminergic neurons with high TRPV1 expression; and a degradation module (β-syn peptide, containing a near-infrared-responsive linker) that binds to the hydrophobic domain of the non-amyloid-β component of α-synuclein, facilitating the degradation of α-syn fibrils.

Using an α-syn fibril-induced PD model, the researchers attempted to restore the degenerated dopaminergic neurons in the substantia nigra of the midbrain through use of the wireless DBS nanosystem.

After stereotactic injection of ATB NPs into the substantia nigra of PD mice, the nanoparticles anchored to the surface of dopaminergic neurons via the TRPV1 antibody. Under 808 nm pulsed near-infrared laser irradiation, they functioned as nanoantennas, converting light into heat to activate the thermosensitive TRPV1 receptor, leading to Ca2+ influx and the generation of action potentials. Meanwhile, they released β-syn peptides, which, through the activation of chaperone-mediated autophagy pathways, cleared α-syn aggregates, reducing pathological fibrils. Ultimately, the ATB NPs restored the interactive network of dopaminergic neurons and their dopamine release capacity, improving motor function in PD mice.

This wireless DBS nanosystem has three primary advantages: It leverages the endogenously expressed TRPV1 receptors in dopaminergic neurons of the substantia nigra, eliminating the need for implanted neural electrodes or genetic manipulation; it enables precise spatiotemporal modulation of degenerative neurons in specific brain regions by integrating near-infrared laser technology; and it exhibits excellent biosafety.

Reference A nanoparticle-based wireless deep brain stimulation system that reverses Parkinson’s disease Junguang Wu, Xuejing Cui, Lin Bao, Guanyu Liu, Xiaoyu Wang, Chunying Chen https://www.science.org/doi/10.1126/sciadv.ado4927 Chinese Academy of Sciences