Nuclear pore complexes (NPCs) selectively mediate all nucleocytoplasmic transport and engage in fundamental cell-physiological processes. It is hypothesized that NPCs are critical for malignant transformation and survival of lung cancer cells, and test the hypothesis in lowly and highly metastatic non-small human lung cancer cells (NSCLCs). It is shown that malignant transformation is paralleled by an increased NPCs density, and a balanced pathological weakening of the physiological stringency of the NPC barrier. Pharmacological interference using barrier-breaking compounds collapses the stringency. Concomitantly, it induces drastic overall structural changes of NSCLCs, terminating their migration. Moreover, the degree of malignancy is found to be paralleled by substantially decreased lamin A/C levels. The latter provides crucial structural and mechanical stability to the nucleus, and interacts with NPCs, cytoskeleton, and nucleoskeleton for cell maintenance, survival, and motility. The recent study reveals the physiological importance of the NPC barrier stringency for mechanical and structural resilience of normal cell nuclei. Hence, reduced lamin A/C levels in conjunction with controlled pathological weakening of the NPC barrier stringency may facilitate deformability of NSCLCs during the metastasis steps. Modulation of the NPC barrier presents a potential strategy for suppressing the malignant phenotype or enhancing the effectiveness of currently existing chemotherapeutics.

Nuclear pore complexes (NPCs) are sophisticated transporters assembled from diverse proteins termed nucleoporins (Nups). They control all nucleocytoplasmic transport and form a stringent barrier between the cytosol and the nucleus. While selective receptor‐mediated transport enables translocation of macromolecules up to striking sizes approaching megadalton‐scale, the upper cutoff for diffusion is at 40 kDa. Raising the cutoff is of particular importance for nuclear delivery of therapeutic nanoparticles, for example, gene and chemotherapy. In this work, we set out to present compounds capable of raising the cutoff to an extent enabling nuclear delivery of 6 kbp pDNA (150 kDa) in cultured human vascular endothelial cells. Of all tested compounds one is singled out, 1,6‐hexanediol (1,6‐HD). Our observations reveal that 1,6‐HD facilitates nuclear delivery of pDNA in up to 10–20% of the tested cells, compared to no delivery at all in control conditions. It acts by interfering with bonds between Nups that occupy the NPC channel and confer transport selectivity. It also largely maintains cell viability even at high concentrations. We envisage that 1,6‐HD may serve as a lead substance and usher in the design of potent new strategies to increase nuclear delivery of therapeutic nanoparticles.