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

Abstract

Salmonella selectively colonizes into the hypoxic tumor region and exerts antitumor effects via multiple mechanisms, while the tumor colonized Salmonella recruits host neutrophils into the tumor, presenting a key immunological restraint to compromise the Salmonella efficacy. Here, we develop a combinatorial strategy by employing silver nanoparticles (AgNPs) to improve the efficacy and biosafety of Salmonella. 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 Salmonella colonized tumor. The tumor-targeting AgNPs exert the functions of (1) local depletion of neutrophils in tumors to boost the efficacy of Salmonella, (2) direct killing tumor cells via L-selectin-mediated intracellular delivery, and (3) clearing the residual Salmonella 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.

Integration of Salmonella into Combination Cancer Therapy

“…The concept of applying nanoparticles to deliver Salmonella proteins is well-accepted in circumventing the safety concern of using infectious agent like Salmonella, but nanoparticles lack the unique feature of Salmonella in the preferential colonization of tumor tissues. A recently published paper utilized nanoparticle technology and Salmonella to enhance the treatment efficacy and safety [194]. They employed silver nanoparticles (AgNPs) conjugated with sialic acid to locally deplete tumor-infiltrating neutrophils through the selective recognition of L-selectin, thereby enhancing the efficacy of Salmonella.…”

Both‐In‐One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem‐Amplifying Reactive Oxygen Species‐Immunity Responses

“…Theoretically, after systemic administration, live bacteria can use their self-propulsion abilities to actively swim away from the vasculature to disperse themselves throughout the tumor tissue. [27] Moreover, the reproductive ability of the engineered bacteria would boost the bacteria-produced cytotoxic protein in the tumor, thereby enhancing the resulting therapeutic outcomes. [28] However, OMVs do not have this ability.…”

Targeting Selectins Mediated Biological Activities With Multivalent Probes

“…Bacterial mediated tumor therapy (BMTT) is an attractive target to cure cancer ( Liu, 2019 ). However, neutrophil recruitment to the tumor site eliminates the bacteria and induces an immunological barrier for BMTT ( Mi et al, 2021 ). As a result, neutrophil-depleting strategies have been employed to improve BMTT cancer therapy.…”

“…As a result, neutrophil-depleting strategies have been employed to improve BMTT cancer therapy. Recently, Rong and co-worked synthesized sialic acid-coated silver nanoparticles to target L-selectin on neutrophils ( Mi et al, 2021 ). These glyco-AgNPs showed neutrophilic depletion and increased salmonella bacteria’s efficacy, which directly killed tumor cells and demonstrated superior therapeutic potentials ( Mi et al, 2021 ).…”