Efficient Colorectal Cancer Gene Therapy with IL-15 mRNA Nanoformulation

Lei, Sibei; Zhang, Xueyan; Men, Ke; Yang, Xijing; Wu, Sisi; Duan, Xingmei; Wei, Yuquan; Tong, Rongsheng

doi:10.1021/acs.molpharmaceut.0c00451

Cited by 51 publications

(39 citation statements)

References 45 publications

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“…Alternatively to vaccination, a pro-inflammatory tumour microenvironment can be induced by lipid nanoparticle–mRNA formulations delivering cytokines or co-stimulatory molecules 33 , 106 , 161 , 163 , 214 (Table 2 ). For example, mRNA-2416, a lipid nanoparticle encapsulating mRNA encoding human OX40L (a ligand of OX40), is in clinical evaluation for the treatment of patients with solid tumours (NCT03323398) 214 .…”

Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

Lipid nanoparticles for mRNA delivery

et al. 2021

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Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle–mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers and possible administration routes for lipid nanoparticle–mRNA systems. We then consider key points for the clinical translation of lipid nanoparticle–mRNA formulations, including good manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies of lipid nanoparticle–mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technology.

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Section: Preclinical Studies and Clinical Trialsmentioning

confidence: 99%

Lipid nanoparticles for mRNA delivery

et al. 2021

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“… 49 Lei et al synthesized a protamine/cationic liposome system to deliver IL15 mRNA, and this complex was able to treat colon cancer in a lung metastatic tumor model by systemic administration. 50 Pardi et al reported that LNP-supported delivery of modified mRNA resulted in high translation rates for a short time by intravenous administration. 51 …”

Section: Discussionmentioning

confidence: 99%

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

Men¹,

Pan²,

Li³

et al. 2021

IJN

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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.

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“…Local or systemic administration of this mRNA induced inhibition of cellular proliferation in several colon cancer models in a safe and efficient way. These results have shown the high therapeutic potential for colorectal cancer immunogenic therapy with this approach [83]. In the same context, Interleukin 2 (IL-2) exerts significant anti-tumor activity.…”

Section: Immunotherapymentioning

confidence: 95%

mRNA, a Revolution in Biomedicine

et al. 2021

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The perspective of using messenger RNA (mRNA) as a therapeutic molecule first faced some uncertainties due to concerns about its instability and the feasibility of large-scale production. Today, given technological advances and deeper biomolecular knowledge, these issues have started to be addressed and some strategies are being exploited to overcome the limitations. Thus, the potential of mRNA has become increasingly recognized for the development of new innovative therapeutics, envisioning its application in immunotherapy, regenerative medicine, vaccination, and gene editing. Nonetheless, to fully potentiate mRNA therapeutic application, its efficient production, stabilization and delivery into the target cells are required. In recent years, intensive research has been carried out in this field in order to bring new and effective solutions towards the stabilization and delivery of mRNA. Presently, the therapeutic potential of mRNA is undoubtedly recognized, which was greatly reinforced by the results achieved in the battle against the COVID-19 pandemic, but there are still some issues that need to be improved, which are critically discussed in this review.

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Efficient Colorectal Cancer Gene Therapy with IL-15 mRNA Nanoformulation

Cited by 51 publications

References 45 publications

Lipid nanoparticles for mRNA delivery

Lipid nanoparticles for mRNA delivery

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

mRNA, a Revolution in Biomedicine

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