Activated T Cell-Derived Exosomes for Targeted Delivery of AXL-SiRNA Loaded Paclitaxel-Poly-L-Lysine Prodrug to Overcome Drug Resistance in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) still lacks effective treatment options due to tumor heterogeneity and immunosuppressive microenvironment caused chemoimmunotherapy therapy resistance. Here, the programmed death ligand-1 (PD-L1) and AXL protein are observed to be overexpressed in the paclitaxel (PTX)-resistant TNBC cell lines. AXL overexpression mediates PTX resistance and immune escape by enhancing the epithelial mesenchymal transition (EMT) process and tumor cell stemness. Hence, an AXL-siRNA (siAXL) loaded glutathione (GSH)-responsive PTX-poly-L-lysine (PTX-PLL; PP) prodrug micelle encapsulated within activated T cellderived exosome delivery system (PP/siAXL@EXO) is developed to overcome the above obstacles. At the tumor site, exosomal PD-1 attenuates PD-L1-induced immune suppression and enhances cellular uptake. In tumor cells, the first released siAXL overcomes PTX resistance by reversing EMT and inhibits T cell exhaustion, and subsequent high GSH-triggered disulfide bond cleavage promotes GSH depletion and PTX release to kill tumor cells. Moreover, AXL knockdown and PTX-PLL prodrugs synergistically induce immunogenic tumor cell death to enhance immune-killing effect mediated by exosomal PD-1, forming a positive feedback anti-tumor immune cycle. PP/siAXL@EXO overcomes TNBC heterogeneity and significantly inhibit PTX-resistance tumor growth and metastasis, and induce protective immune memory with excellent biosafety. Collectively, PP/siAXL@EXO platform, realizing tumor-specific spatiotemporally synchronized gene-chemoimmunotherapy, provides a potential therapeutic strategy for TNBC.