Amplified Ferroptosis and Apoptosis Facilitated by Differentiation Therapy Efficiently Suppress the Progression of Osteosarcoma

Osteosarcoma (OS) is the most frequent osseous neoplasm among young people aged 10-20. Currently, the leading treatment for osteosarcoma is a combination of surgery and chemotherapy. However, the mortality remains high due to chemoresistance, metastasis, and recurrence, attributing to the existence of cancer stem cells (CSCs) as reported. To target CSCs, differentiation therapy attracts increasing attention, inducing CSCs to bulk tumor cells with elevated reactive oxygen species (ROS) levels and less chemoresistance. Moreover, increasing studies have implied that ferroptosis is a promising approach to eliminating cancer cells through eliciting oxidative damage and subsequent apoptosis, effectively bypassing chemoresistance. Here, a cancer-cell-membrane-decorated biocompatible formulation (GA-Fe@CMRALi liposome) is constructed to combat OS efficiently by combining distinct differentiation and ferroptosis therapies through magnified ROS-triggered ferroptosis and apoptosis with homologous target capability to tumor sites. The combinational approach exhibited favorable therapeutic efficacy against OS in vitro and in vivo. Impressively, the potential mechanisms are revealed by mRNA sequencing. This study provides a tactical design and typical paradigm of the synergized differentiation and ferroptosis therapies to combat heterogeneous OS.