Staff member

Targeting the transferrin receptor (TfR) holds promise for drug delivery across the blood-brain barrier (BBB), but conventional strategies suffer from competition with endogenous ligands and suboptimal trafficking. To overcome these limitations, we engineered a library of T7 peptide-functionalised pH-responsive polymersomes with precise control over ligand density and ligand insertion depth (delta) within a poly(ethylene glycol) (PEG) corona. We generated nanoparticles with delta values ranging from 0.3 (deeply inserted ligands) to 1.0 (fully exposed ligands), enabling systematic evaluation of how spatial ligand presentation influences BBB interactions. In vitro studies revealed that delta = 1.0 polymersomes exhibited efficient transcytosis, whereas delta = 0.6 polymersomes promoted endothelial retention, a divergence likely linked to differential receptor clustering and trafficking kinetics. Notably, TfR-mediated transport occurred independently of PACSIN2, distinguishing it from tubular transcytosis pathways observed with LRP1-targeted systems. These findings establish avidity-by-design as a strategy to tailor nanocarriers for either BBB penetration or vascular targeting, offering a modular platform for neurological therapeutics.

JTD Keywords: Brain endothelium, Multivalency, Pacsin2, Ph, Ph-sensitive polymersome, Transcytosis, Transferrin, Transferrin receptor

Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP(3)R2-Ca2+-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation.

JTD Keywords: cd200, contact-dependent, methamphetamine, neuron-to-microglia, psd95, Activation, Cd200, Contact-dependent, Expression, Glutamate, Methamphetamine, Neuron-to-microglia, Neuroprotection, Platform, Psd95