Rationale: Treatment for Parkinson's disease (PD) is challenged by the presence of the blood-brain barrier (BBB) that significantly limits the effective drug concentration in a patient's brain for therapeutic response throughout various stages of PD. Curcumin holds the potential for α-synuclein clearance to treat PD; however, its applications are still limited due to its low bioavailability and poor permeability through the BBB in a free form.Methods: Herein, this paper fabricated curcumin-loaded polysorbate 80-modified cerasome (CPC) nanoparticles (NPs) with a mean diameter of ~110 nm for enhancing the localized curcumin delivery into the targeted brain nuclei via effective BBB opening in combination with ultrasound-targeted microbubble destruction (UTMD).Results: The liposomal nanohybrid cerasome exhibited superior stability towards PS 80 surfactant solubilization and longer circulation lifetime (t1/2 = 6.22 h), much longer than free curcumin (t1/2 = 0.76 h). The permeation was found to be 1.7-fold higher than that of CPC treatment only at 6 h after the systemic administration of CPC NPs. Notably, motor behaviors, dopamine (DA) level and tyrosine hydroxylase (TH) expression all returned to normal, thanks to α-synuclein (AS) removal mediated by efficient curcumin delivery to the striatum. Most importantly, the animal experiment demonstrated that the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder and dopamine depletion during two-week post-observation after treatment with CPC NPs (15 mg curcumin/kg) coupled with UTMD.Conclusion: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future.

We have demonstrated that a typical nanothermometer was incorporated in a bovine serum albumin stabilized gold nanostar-indocyanine green (denoted as GNS-ICG-BSA) nanoprobe to realize surface-enhanced Raman scattering (SERS) imaging-based real-time sensitive monitoring of intracellular temperature in photothermal therapy (PTT), which significantly improved the spatial resolution compared to infrared thermal imaging. Herein, an exogenous thermosensitive molecule, ICG, acting as a tri-functional agent, was selected as the Raman reporter instead of direct cellular biochemical changes. The triggering of the obtained probe was unaffected by the cellular microenvironment, so it can act as a monitor of PTT in various cell types. High-resolution mass spectrometry (HRMS) was used to investigate the thermosensitive mechanism of ICG. The actively targeted GNS-ICG-BSA nanotags were used to induce SERS mapping-guided in vitro PTT of U87 glioma cells. Meanwhile, small temperature variations within a cell during PTT can be precisely monitored through the SERS fingerprint information, with a spatial resolution at the subcellular level and a sensitivity of 0.37 °C. Thus, the integrated GNS-ICG-BSA nanotags can be treated as a theranostic probe, a SERS imaging probe and an intracellular thermometer. Moreover, the good biocompatibility and the low cytotoxicity of GNS-ICG-BSA nanotags, together with their superior photothermal ablation effect on U87 glioma cells have been confirmed. This suggested that the implanted nanothermometry approach would be promising for a better understanding of the biological processes at subcellular level and provide new insights into the fabrication of a multifunctional nanoplatform. Furthermore, this study revealed that the SERS-based monitoring technique can offer great potential for theranostics as an emerging strategy.