Targeting ABCA1 via Extracellular Vesicle‐Encapsulated Staurosporine as a Therapeutic Strategy to Enhance Radiosensitivity

Abstract

AbstractCancer stem cells (CSCs) are essential for tumor initiation, recurrence, metastasis, and resistance. However, targeting CSCs as a therapeutic approach remains challenging. Here, a stemness signature based on 22‐gene is developed to predict prognosis in esophageal squamous cell carcinoma (ESCC). Staurosporine (STS) is identified as a radioresistance suppressor by high‐throughput screening of a library of 2131 natural compounds, leading to dramatically improved radiotherapy efficacy in subcutaneous tumor models. Mechanistically, STS inhibits cell proliferation through the mTOR/AKT signaling pathway and suppressed stemness by targeting ATP‐binding cassette A1 (ABCA1), which is transcriptionally regulated by liver X receptor alpha (LXRα). STS can selectively bind to the nucleotide‐binding domain (NBD) of ABCA1 and compete for ATP, blocking ABCA1‐mediated drug efflux and facilitating intracellular accumulation of STS. Considering the cytotoxicity of STS, an extracellular vesicle‐encapsulated STS system (EV‐STS) is established for effective STS delivery. EV‐STS shows remarkable tumor growth inhibition, even at half the dose of STS, with superior safety and efficacy. These findings indicate that ABCA1 may serve as a predictor of response to neoadjuvant chemotherapy and/or radiotherapy in ESCC patients. EV‐STS has shown improved antitumor efficacy and low systemic toxicity, offering a promising therapeutic approach for ESCC.