TLR Agonist/Copper-Based Metformin Carbon Dot-Loaded Homologous Membrane Nanocarriers with Enhanced Immunogenic Cell Death for Synchronous Amelioration of Tumor Microenvironment Hypoxia, Immunosuppression, and Metastasis Inhibition.

The immunosuppressive tumor microenvironment (TME) and hypoxia are core drivers of tumor metastasis and recurrence. In this study, we constructed a biomimetic delivery system (CMCMCDR) coated with CT26 tumor cell membranes, loaded with copper metformin carbon dots (CuMCDs), doxorubicin (DOX), and Toll-like receptor 7 (TLR7) agonist R837. This system aims to reverse immunosuppression and hypoxia through multimodal synergy, thereby enhancing antitumor efficacy. CMCMCDR exhibits pH-responsive drug release properties. CuMCDs generate •OH and O2 via the copper-Fenton reaction to alleviate hypoxia and achieve chemodynamic therapy (CDT); under 660/808 nm laser irradiation, CuMCDs synergize with photothermal therapy (PTT) and photodynamic therapy (PDT), significantly upregulating the expression of immunogenic cell death (ICD) markers (CRT, HMGB1, ATP). R837 enhances antigen presentation and synergizes with CMCMCDR to promote dendritic cell maturation (upregulation of CD80/CD86) and induce M2-to-M1 macrophage polarization. Meanwhile, it reduces immunosuppressive molecules (HIF-1α, PD-L1) and the anti-inflammatory factor IL-10 while increasing CD4+/CD8+ T cell infiltration and the secretion of pro-inflammatory factors (IL-6, TNF-α). In the dual-tumor model, CMCMCDR targets tumors, inhibits primary tumor growth, and blocks distant metastasis by activating systemic immunity. This study confirms that CMCMCDR synergistically improves hypoxia and immunosuppression through CDT/PTT/PDT and R837-mediated immunoregulation, providing a strategy for combating tumor metastasis and recurrence.