A cascade targeting strategy based on modified bacterial vesicles for enhancing cancer immunotherapy

Abstract

Background As an efficient tumor immunotherapy, PD-1 antibody has been gradually used in clinical tumor treatment, but the low response rate and excessive immune response limit its extensive application. Results Herein, a therapeutic regime for the reinvigoration and activation of the tumor immune microenvironment is introduced to improve the anti-tumor effect of the PD-1 antibody. To comprehensively improve the effect of the immunotherapy and reduce excessive immune response, a biomimetic cascade targeting nanosystem, siRNA@PLOV, which was fused by photothermal sensitive liposomes (PTSLs) and attenuated Salmonella outer membrane vesicles (OMVs), was administered in the tumor therapy for targeting of tumor tissues and T cells within tumor respectively. The fused PLOVs which not only retained the biological character of the OMVs, but also enhanced the drug loading ability. The results demonstrated that the immunogenicity of OMVs and photothermal effects can obviously increase the infiltration of T cells and the silencing of CD38 can effectively improve the T cell cytotoxicity, especially combining with PD-1 antibody. Conclusions Interesting, this study revealed that anti-PD-1 administration on the 5th day after siRNA@PLOV treatment had the best performance in killing tumors compared with other groups. In addition, this new therapeutic regime also presents a novel strategy for inducing “vaccine effects”, conclusively highlighting its potential in preventing tumor recurrence and improving prognosis. Graphical Abstract

Bacterial‐Mediated Tumor Therapy: Old Treatment in a New Context

“…[215] First, OMVs contain many natural adjuvant components inherited from the parent bacterium but in a nonreplicative form, which can stimulate immune maturation and initiate inflammation in a controllable manner. [180] As shown in Figure 13B, the engineered OMV-PD1 specifically expressing PD1 was isolated and purified from E. coli that specifically expressing PD1. OMV-PD1 could bind to PD-L1 on the surface of tumor cells, promote the internalization and reduction of PD-L1, and protect T cells from immunosuppression.…”

Harnessing Engineered Immune Cells and Bacteria as Drug Carriers for Cancer Immunotherapy

“…Zou et al and Li et al both hybridized tumor cell membranes with OMVs to enhance the adaptive tumor immune response. , Moreover, according to Zhang et al, the thylakoid nanovesicle is another great choice to fuse with OMVs since it could enhance antitumor immunity via PDT effect . What’s more, Zhai et al demonstrated that OMVs could also be fused with photothermal sensitive liposomes to deliver siRNA for a combined photo/immunotherapy . Zhou et al developed a micromotor OMV (Figure d) to physically disrupt tumor tissue, recruit immune cells to process antigens from dead tumor cells, and elicit robust antitumor immunity .…”

“…256 What's more, Zhai et al demonstrated that OMVs could also be fused with photothermal sensitive liposomes to deliver siRNA for a combined photo/immunotherapy. 257 Zhou et al developed a micromotor OMV (Figure 9d) to physically disrupt tumor tissue, recruit immune cells to process antigens from dead tumor cells, and elicit robust antitumor immunity. 212 Li et al constructed PD-1-modified E. coli to collect OMV-PD-1 which could simultaneously provoke an immune response and block the PD-1/PD-L1-mediated T-cell exhaustion.…”

Application of lipid nanovesicle drug delivery system in cancer immunotherapy

“…PTSLs can induce ICD by PTT and enhance the function of T cells by CD38 siRNA. Moreover, OMVs can enhance the immune response through their own adjuvant effect [123]. Wang's group and Chen's group both developed OMV-cancer cell member vesicle (OMV-CMV) nanoplatforms with PTT.…”