{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:04:30Z","timestamp":1791597870102,"version":"4.3.4"},"reference-count":128,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brazilian agencies Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","award":["305965\/2024-7"],"award-info":[{"award-number":["305965\/2024-7"]}]},{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Rio de Janeiro","award":["E-26\/200.854\/2025"],"award-info":[{"award-number":["E-26\/200.854\/2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>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\u2013neuron metabolic support. On the other hand, they facilitate the spread of prions and neurodegenerative protein aggregates, such as Tau and \u03b1-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\u2013neuron 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.<\/jats:p>","DOI":"10.3390\/brainsci16020138","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T08:48:04Z","timestamp":1769590084000},"page":"138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tunneling Nanotubes in Astrocyte\u2013Neuron Crosstalk: From Intercellular Communication and Pathological Spread to Mechanobiological and Bio-Inspired Approaches"],"prefix":"10.3390","volume":"16","author":[{"given":"Gustavo","family":"Dias","sequence":"first","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"},{"name":"Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1145-6188","authenticated-orcid":false,"given":"L\u00edvia de S\u00e1","family":"Hayashide","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9737-0568","authenticated-orcid":false,"given":"Bruna","family":"Pessoa","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2986-4043","authenticated-orcid":false,"given":"Luan Pereira","family":"Diniz","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"},{"name":"Instituto de Educa\u00e7\u00e3o M\u00e9dica (IDOMED), Rio de Janeiro 20071-004, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-1204","authenticated-orcid":false,"given":"Bruno","family":"Pontes","sequence":"additional","affiliation":[{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"},{"name":"Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","unstructured":"Caire, M.J., Reddy, V., and Varacallo, M.A. (2025). 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