Coating Dormant Collagenase-Producing Bacteria with Metal-Anesthetic Networks for Precision Tumor Therapy.

Abstract

Tumor malignancy highly depends on the stiffness of tumor matrix, which mainly consists of collagen. Despite the destruction of tumor matrix is conducive to tumor therapy, it causes the risk of tumor metastasis. Here, metal-anesthetic network-coated dormant collagenase-producing Clostridium is constructed to simultaneously destruct tumor matrix and inhibit tumor metastasis. By metal-phenolic complexation and π-π stacking interactions, a Fe3+-propofol network is formed on bacterial surface. Coated dormant Clostridium can selectively germinate and rapidly proliferate in tumor sites due to the ability of carried Fe3+ ions to promote bacterial multiplication. Intratumoral colonization of Clostridium produces sufficient collagenases to degrade tumor collagen mesh and the loaded propofol restrains tumor metastasis by inhibiting tumor cell migration and invasion. Meanwhile, the delivered Fe3+ ions are reduced to the Fe2+ form by intracellular glutathione, thereby inducing potent Fenton reaction to trigger lipid peroxidation and ultimate ferroptosis of tumor cells. In addition to a satisfactory safety, a single intratumoral injection of coated dormant Clostridium not only effectively retards the growth of established large primary tumors, but also significantly suppresses distal lung metastasis in two different orthotopic tumor models. This work proposes a strategy to develop advanced therapeutics for malignant tumor treatment and metastasis prevention.