Visible tumor-targeting biohybrid vehicles reprogram cancer-associated fibroblasts to potentiate photothermal immunotherapy.

Abstract

The extracellular matrix (ECM) is a physical barrier that severely hinders the deep penetration of photothermal agents and immune cells, which is a major challenge to the efficacy of tumor photothermal immunotherapy. In this study, a visible tumor-targeting platelet membrane-wrapped biohybrid vehicle was developed to potentiate photothermalimmunotherapy through cancer-associated fibroblasts (CAFs) reprogramming. This system integrated IR820-modified platelet membrane and manganese-polyphenol nanoparticlesloaded with losartan. Based on the image contrast signals from IR820 and manganese ions, the biohybrid system enabled visual delivery under the guidance of fluorescence-magnetic dual-modal imaging. After reprogramming CAFs to a quiescent state with released losartan, the ECM was remodeled. The attenuated physical barrier and platelet carriers collectively facilitated the deep penetration of photothermal agents, improving the sensitivity of photothermal therapy. Moreover, the synergistic strategy of photothermal stimulation and CAFs regulation simultaneously activated the systemic immunity and alleviated the immunosuppressive tumor microenvironment. The biohybrid delivery system effectively reconstructed the anti-tumor immune defense system to boost the efficacy of photothermal immunotherapy through a positive feedback mechanism. STATEMENT OF SIGNIFICANCE: The dense extracellular matrix (ECM) constitutes a major physical barrier that severely restricts the penetration of photothermal agents and immune cells into tumors, thereby substantially limiting the efficacy of photothermal immunotherapy. A key cause of this barrier is cancer-associated fibroblasts (CAFs), which also suppress immunity. Reverting CAFs to a quiescent state or reprogramming them toward a tumor-suppressive phenotype offers a promising strategy to ameliorate ECM deposition and reverse immunosuppression. A visible tumor-targeting platelet membrane-wrapped biohybrid vehicle was developed to potentiate photothermal-immunotherapy through CAFs reprogramming. This intervention disrupts the stromal barrier and mitigates immune suppression for boosting anti-tumor immunity. Furthermore, the system enables real-time, dual-modal MRI-fluorescence imaging, providing a visual guidance platform for precision photothermal immunotherapy.