Chavali, P. L. | Search bioRxiv

bioRxiv2026

Nanoarchaeosome-mediated epirubicin delivery induces sustained intracellular stress and suppresses adaptive glioblastoma phentoypes

Although anthracyclines such as epirubicin are potent DNA-damaging agents, their application in glioblastoma (GBM) is limited by poor intracellular penetration, lack of durable responses and rapid emergence of adaptive tumor phenotypes. Here, we demonstrate that nanoarchaeosome-mediated delivery of epirubicin (NanoEpi) enables functional reprogramming of GBM survival under therapeutic stress. Nanoarchaeosomes composed of archaeal ether lipids exhibited high encapsulation efficiency ([~]96%) and nanoscale stability. Although both Epi and NanoEpi showed similar bulk uptake, both in established (U251-MG) and patient-derived (Gli5) glioblastoma models, NanoEpi induced significantly greater cytotoxicity than free epirubicin, indicating enhanced intracellular drug engagement. NanoEpi induced enhanced DNA damage, elevated reactive oxygen species, and mitochondrial depolarisation, leading to cytoskeletal collapse. In 3D gliomasphere systems, NanoEpi showed improved penetration and sustained retention, resulting in suppression of core viability and invasion. This correlates with its increased uptake by the lysosomes. Notably, even a transient exposure led to depletion of sphere-initiating capacity and complete loss of clonogenic recovery, indicating targeting of the stem-like compartment. This was accompanied by attenuation of MMP-2/9 activity and reduced angiogenic signalling in a chorioallantoic membrane model. These findings establish nanoarchaeosomes as a robust lysosome-directed delivery platform that extends beyond passive drug transport to sustain intracellular stress and suppress invasive adaptation and limit recurrence in GBM.

cancer biology↗

bioRxiv2024

RNA binding protein Musashi1 interacts with the viral genomic RNA and restricts SARS-CoV-2 infection by repressing translation

Musashi RNA binding proteins are important post-transcriptional regulators of stem cell homeostasis and are known to be involved in viral infections. However, their role in SARS-CoV-2 infection remains largely unknown. Using computational studies, in vivo RNA immunoprecipitation and biochemical assays, here, we establish that Musashi1 (Msi1) interacts with viral genomic RNA through direct binding to the SARS-CoV-2 3UTR. Importantly, binding of Msi1 to the viral 3UTR results in translational repression mediated by inhibition of Poly (A) binding protein (PABP). Conversely, Msi1 knockout promotes robust viral replication and increased viral protein expression. Using 2D cell cultures, stem cells and 3D organoids, we show that depletion of Msi1 in intestinal cells augments infection. This finding explains why the human intestine serves as a reservoir for the SARS-CoV-2 virus, wherein differentiated enterocytes, which have negligible levels of Msi1, are highly affected. Contrarily, stem cells which are enriched for Msi1 expression, are known to be less permissive to SARS-CoV-2 infection despite expressing the entry receptors. Our findings show how translation repression of SARS-CoV-2 by stem cell RNA binding proteins such as Msi1 could help evasion of infection.

cell biology↗