'Pioneer' T cells and 'major force' piezo-nanozymes synergize to achieve high-specificity targeted penetration and enhanced immunotherapy.

The crucial challenge of nanodrug systems is their low transfer efficiency, which requires overcoming transmission resistance due to tumour accumulation and intratumoural penetration. In this study, we propose a synergistic strategy involving 'pioneer' T cells and 'main force' piezo-nanozymes to enhance the ability of T cells and nanodrugs to simultaneously target tumours with high specificity and achieve enhanced immunotherapy. Herein, a mature dendritic cell (DC) membrane was used to encapsulate the piezo-nanozyme MoS2 to form nanodrugs (MDMs). On the basis of the lymphatic homing ability of mature DCs, MDMs can accumulate in tumour-draining lymph nodes to activate T cells and rivets on T cells. T cells subsequently serve as 'pioneers', overcoming circulatory barriers and leading to MDM accumulation in tumours. Furthermore, the piezo-nanozyme MoS2 acts as the 'main force' for reducing tumour interstitial fluid pressure through piezocatalysis, thereby reducing intratumoural penetration resistance and increasing the permeation efficiency of T cells and nanodrugs. Piezocatalysis initiates immunogenic cell death, further enhancing the efficacy of T-cell immune responses, which not only clear the primary tumour but also inhibit tumour metastasis. This study provides a novel strategy and theoretical basis for overcoming biological barriers and improving the effects of chemotherapy and immunotherapy.