Paclitaxel/Luteolin Coloaded Dual‐Functional Liposomes for Esophageal Cancer Therapy

Abstract Combination therapy integrating chemotherapeutic agents with natural bioactive ingredients represents an attractive strategy for esophageal squamous cell carcinoma (ESCC) treatment, yet achieving tumor‐specific co‐delivery remains a critical challenge. Herein, we report that the combination of luteolin (LUT) and paclitaxel (PTX) exerts a remarkable synergy in ESCC treatment, while concurrently alleviating PTX‐induced hepatotoxicity; EA2 aptamer has been identified for its exceptional specificity and strong affinity toward Catenin Alpha 1 protein (CTNNA1) in ESCC cells. Leveraging this specificity, nanosized EA2‐modified pH‐sensitive liposomes (EA2‐PSL‐PTX/LUT) are successfully developed with effective co‐loading, controlled release, and good biostability. EA2‐PSL‐PTX/LUT exhibits stimuli‐triggered release in the acidic tumor microenvironment and facilitates specific cellular uptake and endosomal escape in ESCC cells. In vivo imaging confirms precise tumor localization, deep tumor penetration, and prolonged retention of the nanocarrier. In vitro and in vivo findings validate that the nanocarrier potentiates synergistic inhibitions of PTX and LUT. Notably, EA2‐PSL‐PTX/LUT significantly activates the tumor microenvironment by promoting dendritic cell maturation and T cell infiltration. And the immunosuppressive microenvironment has been remodeled by decreasing myeloid‐derived suppressor cells and regulatory T cell accumulation. This study provides a strategy for precise delivery of combinational chemotherapeutic drugs for ESCC targeted therapy.