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Low-Dose Mildronate-Derived Lipidoids for Efficient mRNA Vaccine Delivery with Minimal Inflammation Side Effects
Jiwei Liu1, Bing Xiao2, Yongle Yang3
1Zhejiang Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China.
Abstract:
mRNA vaccines have been revolutionizing disease prevention and treatment. However, their further application is hindered by inflammatory side effects, primarily caused by delivery systems such as lipid nanoparticles (LNPs). In response to this issue, we prepared cationic lipids (mLPs) derived from mildronate, a small-molecule drug, and subsequently developed the LNP (mLNP-69) comprising a low dose of mLP. Compared with the LNP (sLNP) based on SM-102, a commercially available ionizable lipid, mLNP-69 ensures effective mRNA delivery while significantly reducing local inflammation. In preclinical prophylactic and therapeutic B16-OVA melanoma models, mLNP-69 demonstrated successful mRNA cancer vaccine delivery in vivo, effectively preventing tumor occurrence or impeding tumor progression. The results suggest that the cationic lipids derived from mildronate, which exhibit efficient delivery capabilities and minimal inflammatory side effects, hold great promise for clinical application.
Insights
New lipid nanoparticles (LNPs) derived from mildronate show reduced inflammation for mRNA vaccines. These novel mLNP-69 systems effectively deliver mRNA cancer vaccines, preventing tumor growth in preclinical models.
Area of Science:
- Biotechnology
- Vaccinology
- Nanomedicine
Background:
- Messenger RNA (mRNA) vaccines offer revolutionary potential for disease prevention and treatment.
- Inflammatory side effects, often linked to lipid nanoparticle (LNP) delivery systems, limit the broader application of mRNA technology.
Purpose of the Study:
- To develop a novel LNP delivery system with reduced inflammatory potential for mRNA vaccines.
- To evaluate the efficacy and safety of a new LNP formulation (mLNP-69) derived from mildronate-based cationic lipids (mLPs).
Main Methods:
- Preparation of cationic lipids (mLPs) from mildronate and formulation into mLNP-69.
- Comparative analysis of mLNP-69 with a standard LNP (sLNP) using SM-102.
- In vivo evaluation of mRNA delivery and anti-tumor efficacy in preclinical B16-OVA melanoma models.
Main Results:
- mLNP-69 demonstrated effective mRNA delivery with significantly reduced local inflammation compared to sLNP.
- In preclinical models, mLNP-69 facilitated successful mRNA cancer vaccine delivery, preventing tumor occurrence and impeding tumor progression.
- The mildronate-derived cationic lipids showed efficient delivery capabilities and minimal inflammatory side effects.
Conclusions:
- Mildronate-derived cationic lipids offer a promising platform for developing safer and more effective mRNA delivery systems.
- mLNP-69 represents a significant advancement in LNP technology, potentially overcoming key limitations of current mRNA vaccines.
- These findings suggest a strong potential for clinical translation of mLNP-69 for mRNA-based therapies and vaccines.
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