UM206-targeted nanotherapy delivers homoharringtonine to FZD1-positive osteosarcoma stem cells, inhibiting tumor progression.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, with current standard treatments offering suboptimal survival rates. A critical challenge lies in Osteosarcoma Cancer Stem Cells (OCSCs), which drive tumorigenesis, progression, and therapy resistance due to their self-renewal capacity. Understanding the mechanisms maintaining OCSC stemness and identifying key therapeutic targets are crucial for developing more effective interventions. This study addresses this gap by investigating OCSC transcriptomic features to pinpoint novel targets and delivery strategies.

Researchers systematically analyzed OCSC transcriptomic features using single-cell and longitudinal RNA-sequencing to identify pathways related to OCSC stemness. They screened and validated homoharringtonine as a potent therapeutic agent against osteosarcoma and OCSCs. To enhance efficacy and reduce systemic toxicity, an FZD1-targeted, pH/glutathione dual-responsive nanoplatform was engineered. This nanoplatform utilized the UM206 peptide for high-affinity binding to FZD1 on OCSC-derived tumors, enabling precise drug delivery and tumor microenvironment-triggered release of homoharringtonine in acidic, glutathione-rich niches.

Transcriptomic analysis revealed transcription factor 7 like 1 (TCF7L1)-associated transcriptional activity as a key driver of OCSC stemness. The frizzled class receptor 1 (FZD1)-associated Wnt/β-catenin signaling pathway was identified as a putative upstream regulator. Importantly, FZD1 expression significantly correlated with clinical malignancy progression in osteosarcoma patients. Screening efforts validated homoharringtonine as a potent therapeutic agent against both osteosarcoma and OCSCs. The engineered nanoplatform, leveraging the UM206 peptide's affinity for FZD1, demonstrated precise drug delivery to OCSC-derived tumors. This targeted approach concurrently enabled efficient, tumor microenvironment-triggered release of homoharringtonine, suggesting enhanced therapeutic potential.

FZD1 expression significantly correlated with clinical malignancy progression in osteosarcoma, highlighting its role as a potential therapeutic target.