Chemotherapy-photothermal liposomes modified by DNA-protein network inhibit oral squamous cell carcinoma progression basing on regulating tumor microenvironment.

Oral squamous cell carcinoma (OSCC) is primarily treated by surgery, radiotherapy, and chemotherapy, yet high recurrence/metastasis rates and treatment-associated toxicity remain major challenges. A key barrier is the immunosuppressive tumor microenvironment (TME) rich in cancer-associated fibroblasts (CAFs), which limits drug penetration and compromises therapeutic synergy. To overcome these obstacles, we developed a composite biomimetic nanodelivery system comprising two distinct formulations: platelet membrane-coated liposomes encapsulating berberine (BBR) and ginsenoside Rg3 (RG3) (B@R/PL) for stromal modulation, and liposomes modified with a neutrophil extracellular trap (NET)-derived DNA-protein network co-loading paclitaxel (PTX) and a photothermal agent (PCP) (P&P/NL) for synergistic killing. In vitro studies using a biomimetic co-culture model demonstrated that B@R/PL effectively downregulated α-smooth muscle actin (α-SMA) expression and blocked CAF-mediated tumor cell migration and invasion. Concurrently, P&P/NL achieved synergistic photothermal-chemotherapy under near-infrared irradiation, inducing reactive oxygen species (ROS) bursts and immunogenic cell death (ICD). In vivo experiments in subcutaneous and lung metastasis models confirmed that this combined strategy exhibited excellent tumor targeting capability, significantly inhibiting tumor growth and reducing pulmonary metastatic nodules. Furthermore, the treatment reshaped the immune microenvironment, evidenced by markedly elevated levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-6 (IL-6), alongside decreased interleukin-10 (IL-10) in tumor tissues. Collectively, this TME-programming biomimetic strategy provides a promising approach with clinical translation potential to overcome TME barriers and achieve efficient anti-tumor and anti-metastasis therapy.