Engineered N1 neutrophil-derived vesicles for photothermal-enhanced immunochemotherapy of esophageal cancer

Esophageal squamous cell carcinoma (ESCC) carries a high risk of recurrence and metastasis and is associated with poor prognosis. Chemotherapy remains essential for ESCC treatment. Oxaliplatin (OXA), a third-generation platinum drug, offers advantages in cancer therapy; however, its lack of tumor targeting and high toxicity to normal cells limit clinical efficacy. To address this, we developed photothermal-assisted nanoparticles coated with N1-type neutrophil membranes engineered to express interleukin-21 (IL-21) on their surface and co-loaded with OXA and BMT-BBT (a photosensitizer) (OXA-BMT@ICVs) to enhance tumor killing. Results demonstrated effective uptake of OXA-BMT@ICVs by ESCC cells (KYSE-150) in vitro. This uptake induced immunogenic cell death (ICD) via activation of oxidative stress and mitochondrial dysfunction, further triggering the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. In vivo studies revealed that, combined with photothermal therapy (PTT), OXA-BMT@ICVs accumulated within tumor tissue, enabling targeted release of OXA and BMT-BBT. The combined action of the cytokine IL-21 and the chemotherapeutic drug activated immune responses, promoting dendritic cell (DC) maturation and CD8+ T cell infiltration. This enhanced inflammatory responses and immune-mediated killing while activating the cGAS-STING pathway, thereby inducing ICD. The combination of OXA-BMT@ICVs and PTT significantly inhibited tumor cell proliferation, promoted apoptosis, and suppressed tumor growth in ESCC-bearing mice. This strategy activates potent immune responses, reduces systemic toxicity, exhibits good biocompatibility and safety, and represents a promising approach for ESCC clinical treatment.