iRGD-modified exosomes-delivered BCL6 siRNA inhibit the progression of diffuse large B-cell lymphoma
Qinhua Liu1, Guanrong Dai2, Yi Wu1
1Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Abstract:
Clinical applications of siRNA therapeutics have been limited by the immunogenicity of the siRNA and low efficiency of siRNA delivery to target cells. Recently, evidence have shown that exosomes, endogenous nano-vesicles, can deliver siRNA to the tumor tissues in mice. Here, to reduce immunogenicity, we selected immature dendritic cells (DCs) to produce exosomes. In addition, tumor targeting was achieved by engineering the DCs to express exosomal membrane protein (Lamp2b), fused to av integrin-specific iRGD peptide (CRGDKGPDC). Next, iRGD targeted exosomes (iRGD-Exo) were isolated from the transfected DCs, and then the isolated exosomes were loaded with BCL6 siRNA by electroporation. Our results found that integrin (αvβ3) receptors were highly expressed on OCI-Ly8 cells. In addition, iRGD-Exo showed high targeting ability with avβ3 integrins positive OCI-Ly8 cells. Significantly, iRGD-Exo loaded with BCL6 siRNA suppressed DLBCL cell proliferation in vitro. Furthermore, intravenously injected iRGD-Exo delivered BCL6 siRNA to tumor tissues, resulting in inhibition of tumor growth in DLBCL. Meanwhile, exosomes mediated BCL6 siRNA delivery did not exhibit appreciable toxicity in mice. Collectively, our study demonstrates a therapeutic potential of exosomes as a promising vehicle for RNAi delivery to treat DLBCL.
Insights
Engineered exosomes effectively deliver BCL6 siRNA to target cells, suppressing Diffuse Large B-cell Lymphoma (DLBCL) growth in mice without significant toxicity. This novel RNAi delivery system shows therapeutic promise for DLBCL treatment.
Area of Science:
- Biotechnology
- Nanomedicine
- Oncology
Background:
- siRNA therapeutics face challenges with immunogenicity and inefficient delivery.
- Exosomes, as natural nanovesicles, show potential for siRNA delivery to tumors.
- Targeted delivery is crucial for enhancing therapeutic efficacy and reducing side effects.
Purpose of the Study:
- To develop an exosome-based delivery system for siRNA targeting Diffuse Large B-cell Lymphoma (DLBCL).
- To engineer exosomes for reduced immunogenicity and enhanced tumor targeting.
- To evaluate the efficacy and safety of BCL6 siRNA loaded exosomes in DLBCL treatment.
Main Methods:
- Immature dendritic cells (DCs) were engineered to produce exosomes displaying iRGD peptide for tumor targeting.
- Exosomes (iRGD-Exo) were isolated and loaded with BCL6 siRNA via electroporation.
- Targeting ability, in vitro efficacy, in vivo tumor inhibition, and toxicity were assessed in DLBCL models.
Main Results:
- Engineered exosomes demonstrated high targeting affinity for αvβ3 integrin-positive DLBCL cells (OCI-Ly8).
- BCL6 siRNA-loaded exosomes significantly suppressed DLBCL cell proliferation in vitro.
- Intravenous administration of exosomes inhibited DLBCL tumor growth in vivo with no apparent toxicity in mice.
Conclusions:
- Engineered exosomes represent a promising, low-immunogenicity platform for targeted RNA interference (RNAi) delivery.
- This exosome-mediated siRNA delivery system effectively targets and inhibits DLBCL growth.
- The study highlights the therapeutic potential of exosomes for treating DLBCL and other cancers.
