Sialidase-Chimeric\nBioengineered Bacteria for Tumor-Sialoglycan-Triggered\nSolid Tumor Therapy

Adoptive cell therapies for solid tumors are usually\nlimited by\noff-target antigens, incapable tissue infiltration, and cell function\nexhaustion. In contrast, bacterial cells possess the inherent competencies\nof preferential tumor targeting, deep tissue penetration, and high\nintratumoral bioactivity and represent promising alternatives to overcome\nthese challenges. Here, a sialic-acid-responsive regulatory gene circuit\nis engineered into <i>Escherichia coli</i> MG1655 to express\ncytolysin of hemolysin E (HlyE). Furthermore, sialidases are bioorthogonally\ndecorated onto the surface of azido-functionalized bioengineered bacteria\nfor recognizing tumor sialoglycans and cleaving their sialosides into\nfree sialic acids. As chemical inducers, sialic acids feedbackingly\nactivate the bacterial gene circuit to produce HlyE and lyse tumor\ncells. This study mimics the tumor antigen-induced cytotoxin production\nand cell lysis that occurs in chimeric antigen receptor T (CAR-T)\ncells yet surmounts the intrinsic limitations of adoptive cell therapies.\nMoreover, sialidase-mediated tumor cell desialylation also reverses\nthe immunosuppressive effect of glycoimmune checkpoints and further\nimproves the therapeutic effect of solid tumors.