The trojan horse strategy in T-ALL therapy by engineering T-ALL-derived exosomes for targeted delivery of Isoliquiritigenin to the bone marrow to conquer Drug-Resistant T-ALL in PDX model

Schematic diagrams of the Exo-ISL Overcoming T-ALL Drug Resistance. Exosomes (Exo) isolated from drug-resistant T-ALL strain CEM-C1 cells via ultracentrifugation encapsulated ISL (Exo-ISL) using ultrasound. Injected intravenously into mice, Exo-ISL targeted and enriched in bone marrow, inducing T-ALL cell death via increased intracellular reactive oxygen species, DNA damage, autophagy, and apoptosis, thereby overcoming T-ALL drug resistance. • Exosomes secreted by T-ALL resistant cells themselves serve as an important means of communication between cells. We use the homing effect of exosomes as a drug delivery platform to deceive tumor cells into accurately and abundantly ingesting drug molecules, thereby achieving highly selective and bone marrow targeting, much like a Trojan horse. • ISL is a natural flavonoid compound known for its safety and diverse health benefits. We utilize exosomes to deliver ISL for the treatment of T-ALL. The experimental results demonstrate its efficacy, thereby broadening the potential applications of ISL. • Issues of drug resistance and relapse further complicate T-ALL treatment. ISL induces cytotoxicity through mechanisms such as apoptosis, autophagy, and DNA damage, offering a novel therapeutic agent for overcoming drug-resistant leukemia, particularly in pediatric patients. This holds significant potential for improving clinical treatment outcomes. • We evaluated the in vivo efficacy of ISL and Exo-ISL against drug-resistant T-ALL cells usingpatient-derived (PDX) xenograft model of drug-resistant T-ALL. Given the significance of PDX models in clinical drug testing, this study establishes a basis for the clinical application and translation of ISL. T-cell acute lymphoblastic leukemia (T-ALL) is often associated with poor prognosis due to high rates of drug resistance and relapse. In this study, the researchers developed a Trojan horse nanotherapeutic strategy that leverages exosomes produced by T-ALL cells to deliver Isoliquiritigenin (ISL) to conquer drug resistant T-ALL. This innovative exosomal drug delivery platform, derived from T-ALL resistant cell lines, is recognized and absorbed by leukemia cells in vivo , enabling targeted enrichment in the bone marrow. Consequently, it facilitates the delivery and release of ISL (the ’soldier’), aiming to enhance therapeutic selectivity and overcome drug resistance. The anticancer effects of ISL and exosome-encapsulated ISL (Exo-ISL) on drug-resistant T-ALL cells were evaluated through biological assays, cell line-derived xenograft (CDX), and patient-derived xenograft (PDX) models. To elucidate the underlying mechanisms, RNA sequencing, acridine orange staining, comet assays, and γ-H2AX immunofluorescence were performed. Our findings demonstrate that T-ALL-derived exosomes significantly enhance the targeted delivery of ISL to the bone marrow. Furthermore, ISL’s effects on drug-resistant T-ALL have been found to involve multiple mechanisms, including induction of apoptosis, DNA damage, and autophagy.