Bioengineered Hybrid Nanovesicles Modulate the Immune Microenvironment with Targeted Drug Delivery for Esophageal Squamous Cell Carcinoma Therapy

Combining chemotherapy and immunotherapy shows great promise for treating esophageal squamous cell carcinoma (ESCC), but its effectiveness is hindered by the immunosuppressive tumor environment and challenges in drug delivery. Recent research has focused on cell membrane-coated nanoparticles for targeted drug delivery, leveraging their ability to evade the immune system while selectively targeting tumor cells. In this study, we developed a biomimetic hybrid nanoplatform based on cell membranes to combine molecular chemotherapy and improve the effectiveness of immunochemotherapy in treating ESCC. The nanoplatform is coated with a membrane fusion of activated neutrophils and ESCC cells and loaded with paclitaxel (PTX) and small interfering RNA targeting EFNA1 (siEFNA1), a molecule linked to ESCC metastasis. By exploiting the homologous targeting properties of ESCC cell membranes and the tumor-homing ability of neutrophil membranes, the platform effectively targets ESCC tissues and delivers siEFNA1 and PTX. This allows for a synergistic treatment approach, combining EFNA1 gene silencing with PTX-induced cytotoxicity to target ESCC more effectively. Crucially, the nanoplatform reprograms tumor-associated macrophages from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype while boosting T cell-mediated cytotoxicity and remodeling the immunosuppressive tumor microenvironment. Overall, this strategy presents a promising approach for the targeted treatment of ESCC.