Menthol-functionalized polyphenol‑copper nanoparticles for spatiotemporally modulable blood-brain barrier permeability and multimodal therapeutics-triggered immune response against glioblastoma

The blood-brain barrier (BBB) significantly impedes the delivery of most drugs to brain tumor sites, while the infiltrative nature of glioblastoma (GBM) complicates treatment with a single therapeutic approach. Drawing inspiration from Traditional Chinese Medicine Theory of “resuscitation with aromatics” and “synergistic interaction”, luteolin (Lut) was coordinated with Cu²⁺ and further functionalized with menthol (M) to construct M@Lut-Cu nanoparticles (MLC NPs) capable of spatiotemporally modulable BBB permeability. The metal coordination endows MLC NPs with photothermal properties and the ability to generate reactive oxygen species (ROS), enabling photothermal therapy (PTT) and chemodynamic therapy (CDT). In combination with cuproptosis, these effects co-stimulate the release of damage-associated molecular patterns (DAMPs), thereby inducing robust immunogenic cell death (ICD). Moreover, the photoacoustic (PA) signals emitted by MLC NPs not only facilitate precision-guided therapy but also enable real-time visualization of the temporal and spatial dynamics of MLC NPs in vivo, demonstrating the ability to modulate BBB permeability in a spatiotemporally modulable manner. Thus, this straightforward approach of coordinating and assembling active ingredients presents an innovative strategy for brain-targeted drug delivery and establishes a transformative paradigm for treating complex and severe brain diseases.