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Engineered extracellular vesicle with RAGE-antagonist peptide for delivery of anti-miRNA155 oligonucleotides to
Chuanyu Zhuang1, Minji Kang1, Jihun Oh1
1Department of Bioengineering, Hanyang University, Seoul, Republic of Korea.
Abstract:
Acute lung injury (ALI) is an inflammatory lung disease. In lungs afflicted with ALI, microRNA-155 (miR-155) is over-expressed, inducing pro-inflammatory cytokines by inhibition of suppressor of cytokine signalling 1 (SOCS1). In addition, receptor for advanced glycation endproducts (RAGEs) are activated, facilitating the expression of pro-inflammatory cytokines. Therefore, anti-miRNA-155 oligonucleotides (AMO155) and a RAGE-antagonist peptide (RAP) have been suggested as effective therapeutics of ALI. In this study, extracellular vesicles (EVs) were developed as a carrier of AMO155 and the RAP for a combination therapy of ALI. RAP-engineered EVs (RAP-EVs) were produced by the expression of a recombinant RAP-Lamp2b fusion protein on the surface. Then, cholesterol-modified AMO155 (AMO155c) was loaded onto the RAP-EV. In vitro assays showed that the RAP-EV delivered AMO155c as efficiently as unmodified EV (Unmod-EV). For in vivo animal experiments, AMO155c-loaded EVs (AMO155c/EVs) were administrated into the ALI models by intratracheal instillation. The results showed that the AMO155c/RAP-EV induced SOCS1 and decreased RAGE expression more efficiently than the control systems. Compared to the controls, the inflammatory responses, such as pro-inflammatory cytokines, were effectively reduced by the AMO155c/RAP-EV. The results indicated that the RAP-EV could be an efficient carrier for the combination therapy of the RAP and AMO155c.
Insights
Engineered extracellular vesicles efficiently deliver combination therapy for acute lung injury (ALI). This novel approach targets microRNA-155 and RAGE, reducing inflammation and improving therapeutic outcomes in ALI models.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Respiratory Medicine
Background:
- Acute lung injury (ALI) is characterized by inflammation and over-expression of microRNA-155 (miR-155), which inhibits SOCS1.
- Receptors for advanced glycation end-products (RAGEs) are activated in ALI, further promoting inflammation.
- Current therapeutic strategies for ALI include targeting miR-155 with anti-miRNA oligonucleotides (AMO155) and inhibiting RAGE with RAGE-antagonist peptides (RAP).
Purpose of the Study:
- To develop extracellular vesicles (EVs) as a dual-delivery system for a combination therapy of AMO155 and RAP for ALI.
- To engineer EVs to display RAP on their surface (RAP-EVs) and load them with cholesterol-modified AMO155 (AMO155c).
- To evaluate the efficacy of RAP-EVs carrying AMO155c (AMO155c/RAP-EV) in vitro and in vivo for ALI treatment.
Main Methods:
- Engineered RAP-EVs by expressing a RAP-Lamp2b fusion protein on the EV surface.
- Loaded AMO155c onto RAP-EVs and compared delivery efficiency with unmodified EVs (Unmod-EVs) in vitro.
- Administered AMO155c/EVs intratracheally into ALI animal models and assessed SOCS1 and RAGE expression, and inflammatory cytokine levels.
Main Results:
- RAP-EVs demonstrated efficient delivery of AMO155c in vitro, comparable to Unmod-EVs.
- In vivo, AMO155c/RAP-EV treatment significantly increased SOCS1 expression and decreased RAGE expression in ALI models.
- A marked reduction in pro-inflammatory cytokine levels was observed in ALI models treated with AMO155c/RAP-EV compared to controls.
Conclusions:
- RAP-engineered EVs serve as an effective carrier for delivering AMO155c and RAP in combination therapy for ALI.
- This combination therapy strategy shows promise in mitigating inflammatory responses associated with acute lung injury.
- EV-based drug delivery systems offer a viable platform for synergistic therapeutic approaches in treating complex lung diseases.
