Hypoxia-Responsive Retinoid Liposomes for Tumor Microenvironment-Activated Differentiation and Metastasis Suppression

Cancer stem-like cells (CSCs) are a key driving factor of tumor heterogeneity, metastasis, and chemoresistance. All-trans retinoic acid (ATRA) shows strong potential for inducing CSC differentiation and reducing stemness; however, its clinical translation is limited by the lack of effective targeting and favorable biodistribution under physiological conditions. Here, we report a hypoxia-responsive ATRA-phospholipid conjugate (RAPC) as a delivery and differentiation-priming strategy, enabling the fabrication of ATRA-loaded liposomes (ATRA@Lip) with high drug loading and microenvironment-activated release. RAPC was synthesized via a modular route incorporating an azobenzene-based hypoxia-cleavable linker between ATRA and a phosphatidylcholine analog. By coassembling RAPC with cholesterol and phospholipid, stable liposomes were obtained with a maximal ATRA loading of 17 wt % at 50 mol % RAPC content. Under normoxia, ATRA@Lip exhibited minimal leakage, whereas hypoxic conditions triggered rapid azo bond cleavage and accelerated ATRA release. Functionally, hypoxia-triggered ATRA@Lip promoted CSC differentiation and enhanced the chemosensitivity of breast cancer cells to albumin-bound paclitaxel (Nab-PTX) in vitro. Collectively, this hypoxia-responsive lipid-drug conjugate platform enables functional CSC priming and improved combination chemotherapy, offering a promising strategy for microenvironment-activated modulation of CSC-associated chemoresistance in metastatic breast cancer.