# Tunneling Nanotubes in Astrocyte–Neuron Crosstalk: From Intercellular Communication and Pathological Spread to Mechanobiological and Bio-Inspired Approaches

## TL;DR

Tunneling nanotubes help cells communicate and transfer materials, but they can also spread harmful proteins linked to diseases like Alzheimer's and Parkinson's.

## Contribution

This paper integrates molecular and mechanobiological insights to clarify the dual role of tunneling nanotubes in health and disease.

## Key findings

- TNTs support homeostasis by transferring mitochondria and supporting neurons.
- TNTs can spread neurodegenerative proteins like Tau and α-synuclein.
- New 3D models and mechanobiological tools improve TNT study in complex tissues.

## Abstract

Tunneling nanotubes (TNTs) are dynamic cell surface conduits that enable direct transfer of ions, signaling molecules, and organelles. They have emerged as a key mechanism of intercellular communication, complementing classical pathways such as synapses and paracrine signaling. In the central nervous system (CNS), TNTs exhibit a functional duality, particularly under aging and stress, where TNT-mediated exchange may shift from protective to maladaptive. On one hand, TNTs support homeostatic functions, ranging from mitochondrial transfer to stem cell-mediated rescue and astrocyte–neuron metabolic support. On the other hand, they facilitate the spread of prions and neurodegenerative protein aggregates, such as Tau and α-synuclein, with astrocytes playing a regulatory role. Despite rapid advances, TNT research faces challenges from conceptual heterogeneity and experimental standardization, especially in complex tissues such as the CNS. Recent mechanobiological and bio-inspired approaches, including force-based assays and three-dimensional culture models, provide new insights into TNT formation, stability, and cargo transport, extending beyond neural systems. This review offers an integrative synthesis of molecular, structural, and mechanobiological principles underlying TNT-mediated communication, emphasizing astrocyte–neuron crosstalk, while proposing validation criteria to support rigor, reproducibility, and cross-study comparability. TNTs thus emerge as dynamic, context-dependent interfaces with broad relevance to neurodegeneration, cancer, and biomedical applications.