“Trojan Horse” Salmonella Enabling Tumor Homing of Silver Nanoparticles via Neutrophil Infiltration for Synergistic Tumor Therapy and Enhanced Biosafety

Abstract

<i>Salmonella</i> selectively colonizes into the hypoxic tumor region and exerts antitumor effects via multiple mechanisms, while the tumor colonized <i>Salmonella</i> recruits host neutrophils into the tumor, presenting a key immunological restraint to compromise the <i>Salmonella</i> efficacy. Here, we develop a combinatorial strategy by employing silver nanoparticles (AgNPs) to improve the efficacy and biosafety of <i>Salmonella</i>. The AgNPs were decorated with sialic acid (SA) to allow selective recognition of L-selectin on neutrophil surfaces, based on which the tumor-homing of AgNPs was achieved by neutrophil infiltration in the <i>Salmonella</i> colonized tumor. The tumor-targeting AgNPs exert the functions of (1) local depletion of neutrophils in tumors to boost the efficacy of <i>Salmonella</i>, (2) direct killing tumor cells via L-selectin-mediated intracellular delivery, and (3) clearing the residual <i>Salmonella</i> after complete tumor eradication to minimize the side effects. With a single tail vein injection of such combination treatment, the tumor was eliminated with high biosafety, resulting in a superior therapeutic outcome.