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<p>Nanoparticles traverse the blood–brain barrier (BBB) through passive diffusion and vesicular transcytosis, but the quantitative contributions of these routes remain difficult to determine. Here, we combine a controlled in-vitro human BBB model (hCMEC/D3 Transwells) with a physics-informed neural network (PINN) to interpret transport kinetics and estimate paracellular and vesicular components. Monodisperse polystyrene nanoparticles (20, 50 and 120&#xa0;nm) showed low polydispersity, stable ζ-potential and minimal cytotoxicity. Intact monolayers displayed high TEER and low tracer permeability, whereas TNF-α induced reversible junctional opening. Apical-to-basolateral transport increased with junctional loosening and remained size-dependent; clathrin and dynamin inhibition reduced flux without altering TEER or tracer passage. A mass-balance-constrained PINN incorporating a TEER-linked permeability term reproduced transport profiles and generalized to combined perturbation (TNF-α + chlorpromazine). Under our conditions, the model suggested that vesicular uptake represented the major route, with a smaller diffusion component that increased during junctional disruption and clathrin inhibition. Overall, this combined experimental–computational approach provides a practical framework for pathway-informed evaluation of nanoparticle transport across the BBB.</p> Graphical Abstract <p></p>

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A physics-informed neural network framework for quantitative analysis of transcytosis and physical diffusion in an in vitro BBB

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月9日

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  • Xin Wang,
  • Bingyan Shen,
  • Wenyuan Yang,
  • Xiao Wang,
  • Changwei Li,
  • Haigang Wu

摘要

Nanoparticles traverse the blood–brain barrier (BBB) through passive diffusion and vesicular transcytosis, but the quantitative contributions of these routes remain difficult to determine. Here, we combine a controlled in-vitro human BBB model (hCMEC/D3 Transwells) with a physics-informed neural network (PINN) to interpret transport kinetics and estimate paracellular and vesicular components. Monodisperse polystyrene nanoparticles (20, 50 and 120 nm) showed low polydispersity, stable ζ-potential and minimal cytotoxicity. Intact monolayers displayed high TEER and low tracer permeability, whereas TNF-α induced reversible junctional opening. Apical-to-basolateral transport increased with junctional loosening and remained size-dependent; clathrin and dynamin inhibition reduced flux without altering TEER or tracer passage. A mass-balance-constrained PINN incorporating a TEER-linked permeability term reproduced transport profiles and generalized to combined perturbation (TNF-α + chlorpromazine). Under our conditions, the model suggested that vesicular uptake represented the major route, with a smaller diffusion component that increased during junctional disruption and clathrin inhibition. Overall, this combined experimental–computational approach provides a practical framework for pathway-informed evaluation of nanoparticle transport across the BBB.

Graphical Abstract