Multipronged SMAD pathway targeting by lipophilic poly(β-amino ester) miR-590-3p nanomiRs inhibits mesenchymal glioblastoma growth and prolongs survival

• DOI: 10.1038/s41392-025-02223-w
• Publication Date: 2025-04-29T23:03:36Z
• Authors: Jack Korleski; Sophie Sall; Kathryn M. Luly; Maya K. Johnson; Amanda L. Johnson; Harmon Khela; Bachchu Lal; TC Taylor; Jean Micheal Ashby; Hector Alonso; Alice Li; Weiqiang Zhou; Karen Smith-Connor; Russell Hughes; Stephany Y. Tzeng; John Laterra; Jordan J. Green; Hernando Lopez-Be...
• Keywords: Reprogramming; Temozolomide

Asbstract Despite aggressive therapy, glioblastoma (GBM) recurs in almost all patients and treatment options are very limited. our growing understanding of how cellular transitions associate with relapse GBM, critical gaps remain ability to block these molecular changes treat recurrent disease. In this study we combine computational biology, forward-thinking miRNA biology cutting-edge nucleic acid delivery vehicles advance targeted therapeutics for GBM. Computational analysis RNA sequencing from clinical GBM specimens identified TGFβ type II receptor (TGFBR2) as a key player the mesenchymal transition associated worse outcome Mechanistically, show that elevated levels TGFBR2 is conducive reduced temozolomide (TMZ) sensitivity. This effect is, at least partially, induced by stem-cell driving events coordinated reprogramming transcription factors Oct4 Sox2 lead open chromatin states. We blocking via pharmacological approaches decreases stem cell capacity sensitivity (rGBM) isolates TMZ vitro. Network uncovered miR-590-3p tumor suppressor simultaneously inhibits multiple oncogenic nodes downstream TGFBR2. also developed novel biodegradable lipophilic poly(β-amino ester) nanoparticles (LiPBAEs) vivo microRNA (miRNAs) delivery. Following direct intra-tumoral infusion, nanomiRs efficiently distribute through tumors. Importantly, inhibited growth extended survival mice bearing orthotopic human rGBM xenografts, an apparent 30% cure rate. These results miRNA-based provide new opportunities bypass resistance standard care therapy.