Interstitial transport of fluids and solutes in the brain plays a central role in maintaining physiological homeostasis, including nutrient supply, metabolic waste clearance, and drug delivery. Impairment of this transport is associated with defective metabolite clearance and has been implicated in neurological disorders such as Alzheimer’s disease, as well as in the pathophysiology and secondary injury processes of stroke. However, our understanding of the mechanisms governing these processes and their influence on brain function and disease remains incomplete and, in some respects, controversial. This is largely due to the complexity of the coupled bio-physico-chemical transport processes, which span multiple length and time scales and are difficult to characterise comprehensively with existing techniques. Here, we present newly developed multiscale, multiphysics models to investigate fluid and particle transport in the brain across scales. At the cellular scale, we developed a versatile microstructure generation framework (MicroFiM) for brain white matter and related fibrous biomaterials with complex microarchitecture and low porosity. Based on reconstructed microstructures, we developed computational models to capture particle–axon and fluid–axon interactions. These models yield: (i) quantitative relationships between nanoparticle size and surface charge and their effective diffusion coefficients in white matter, providing a basis for the design of nanomedicines and nanocarriers for brain delivery [1–3]; and (ii) evidence that axon–fluid interactions are strong and play a critical role in brain fluid and mass transport, indicating that the common assumption of a mechanically rigid microstructure may break down under elevated local hydraulic pressures [4,5]. By upscaling these interactions to the tissue scale, we characterised particle diffusion coefficients in different brain tissues and derived a pressure- and microstructure-dependent permeability tensor for white matter. Building on this, we propose the first anisotropic, pressure-dependent permeability tensor informed by microstructural dynamics for improved macroscale brain modelling, and analyse the influence of key microstructural parameters [5]. Finally, we introduce an anisotropic poro-hyperelastic model coupled to the newly defined porosity–permeability relationship [6], enabling accurate prediction of macroscale permeability changes arising from microstructural deformation during infusion.