Functionalized DMP-039 Hybrid Nanoparticle as a Novel mRNA Vector for Efficient Cancer Suicide Gene Therapy

Abstract

Background Gene therapy has emerged as a new strategy for cancer therapy. As an alternative nucleic acid material, messenger ribonucleic acid (mRNA) is being increasingly utilized in cancer gene therapy. However, unfulfilled requirements and a lack of ideal mRNA delivery vectors persist. Methods We developed an advanced mRNA delivery system, DMP-039, by fusing a cell-penetrating peptide, cRGD-R9, and a cationic nano-sized DMP backbone together. The DMP gene vector backbone was synthesized by the self-assembly of DOTAP lipid and mPEG-PCL polymer. Introduction of the cRGD-R9 peptide onto the DMP backbone was performed to elevate the mRNA delivery capacity, which resulted in a peptide-functionalized hybrid delivery system. Results The average size of the synthesized DMP-039 was 268.9 ± 12.4 nm (PDI = 0.382), with a potential of 17.4 ± 0.5 mV. The synthesized DMP-039 hybrid nanoparticles exhibited high mRNA delivery efficiency through multiple mechanisms during transmembrane transportation. By loading the encoding mRNA from the suicide gene Bim, a locally administered mBim/DMP-039 complex strongly inhibited growth in two colon cancer models. Moreover, intravenous administration of the mBim/DMP-039 complex efficiently suppressed C26 pulmonary metastatic tumor progression with high safety. The in vivo distribution, degradation, and excretion were also investigated in detail. Conclusion Our results suggest that the DMP-039 peptide-functionalized hybrid nanoparticle is an advanced candidate for mRNA-based suicide gene therapy.

Advances in Nanoparticles for Effective Delivery of RNA Therapeutics

“…As a result, modification of the cRGD-R9 peptide significantly promoted mRNA internalization into cancer cells and anti-cancer solid effects in numerous colon-cancer models (Fig. 6c) [88].…”

Suicide gene strategies applied in ovarian cancer studies

“…In the context of ovarian cancer, mRNA is applied mostly in anticancer vaccination or immunomodulationrelated strategies (ClinicalTrials.gov Identifier: NCT04163094 and NCT01334047). Suicide mRNAs have been investigated in other cancers [105][106][107]. However, their application in OC remains to be delineated.…”

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

“…For the example of peptide-polymer-lipid hybrid NPs, by fusing cRGD-R9 (a CPP) and a DMP gene vector backbone synthesized from a combination of DOTAP lipids and mPEG–PCL polymers, Gao et al developed an advanced mRNA delivery system, DMP-039. By investigating the in vivo distribution, degradation, and excretion of the mBim/DMP-039 complex in detail, they concluded that the synthesized DMP-039 hybrid NPs possess high mRNA delivery capacity and good safety profile while showing effective suppression of pulmonary metastatic tumor progression [ 148 ].…”