Lorico Aurelio, Santos Mark F, Karbanová Jana, Corbeil Denis
Department of Basic Sciences, College of Osteopathic Medicine, Touro University Nevada, Henderson, NV 89014, U.S.A.
Biotechnology Center (BIOTEC), Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Saxony, Germany.
Biochem Soc Trans. 2025 Jun 30;53(3):529-546. doi: 10.1042/BST20253005.
Intercellular communication is an essential hallmark of multicellular organisms for their development and adult tissue homeostasis. Over the past two decades, attention has been focused on communication mechanisms based on various membrane structures, as illustrated by the burst of scientific literature in the field of extracellular vesicles (EVs). These lipid bilayer-bound nano- or microparticles, as vehicle-like devices, act as regulators in various biological and physiological processes. When EVs are internalized by recipient cells, their membrane and cytoplasmic cargoes can interfere with cellular activities, affecting pathways that regulate cell proliferation, differentiation, and migration. In cancer, EVs can transfer oncogenic factors, stimulate neo-angiogenesis and immunosuppression, reprogram stromal cells, and confer drug resistance traits, thereby remodeling the surrounding microenvironment. Although the mechanisms underlying EV biogenesis and uptake are now better understood, little is known about the spatiotemporal mechanism(s) of their actions after internalization. In this respect, we have shown that a fraction of endocytosed EVs reaches the nuclear compartment via the VOR (VAP-A-ORP3-Rab7) complex-mediated docking of late endosomes to the outer nuclear membrane in the nucleoplasmic reticulum, positioning and facilitating the transfer of EV cargoes into the nucleoplasm via nuclear pores. Here, we highlight the EV heterogeneity, the cellular pathways governing EV release and uptake by donor and recipient cells, respectively, and focus on a novel intracellular pathway leading to the nuclear transfer of EV cargoes. We will discuss how to intercept it, which could open up new avenues for clinical applications in which EVs and other small extracellular particles (e.g., retroviruses) are implicated.
细胞间通讯是多细胞生物发育和成年组织内稳态的一个基本特征。在过去二十年中，注意力一直集中在基于各种膜结构的通讯机制上，细胞外囊泡（EVs）领域的大量科学文献就说明了这一点。这些脂质双层包裹的纳米或微粒，就像类似载体的装置，在各种生物和生理过程中充当调节因子。当EVs被受体细胞内化时，它们的膜和细胞质货物可以干扰细胞活动，影响调节细胞增殖、分化和迁移的途径。在癌症中，EVs可以转移致癌因子，刺激新血管生成和免疫抑制，重编程基质细胞，并赋予耐药特性，从而重塑周围的微环境。尽管现在对EV生物发生和摄取的潜在机制有了更好的理解，但对于它们内化后作用的时空机制知之甚少。在这方面，我们已经表明，一部分内吞的EVs通过VOR（VAP-A-ORP3-Rab7）复合物介导的晚期内体与核质网中外核膜的对接到达核区室，定位并促进EV货物通过核孔转移到核质中。在这里，我们强调了EV的异质性，分别控制供体细胞释放EV和受体细胞摄取EV的细胞途径，并关注一条导致EV货物核转移的新的细胞内途径。我们将讨论如何阻断它，这可能为涉及EVs和其他细胞外小颗粒（如逆转录病毒）的临床应用开辟新途径。
