Lipid Nanoparticle Drug Delivery Advances April 1-7, 2025

LNP Diagram

Summary of Key Developments

• Sanofi: Published research in Nanoscale on optimizing PEGylated lipids for enhanced mRNA delivery efficacy and stability.

• University of Pennsylvania: Developed nitro-oleic acid-modified LNPs for safer plasmid DNA delivery, enabling long-term gene expression in mice.

• East China Normal University/YolTech Therapeutics: Demonstrated single-dose CRISPR-LNP therapy efficacy in mouse models of primary hyperoxaluria type 1 (PH1).

• Icahn School of Medicine at Mount Sinai: Engineered LNPs capable of crossing the blood-brain barrier to deliver mRNA via intravenous injection.

• ACS Biochemistry Study: Introduced click chemistry LNPs for targeted mRNA delivery to metabolically labeled cancer cells.

Detailed News Summaries

Sanofi: PEGylated Lipid Optimization for mRNA Delivery

Release Date: April 3, 2025

Website Link: https://pubs.rsc.org/en/content/articlelanding/2025/nr/d5nr00433k

Authors: Jae-Heon Kim, Lingyun Liu, et al.

Related Institution: Sanofi mRNA Center of Excellence (Cambridge, MA, USA)

Sanofi researchers published a study in *Nanoscale* detailing advancements in lipid nanoparticle (LNP) formulations for mRNA delivery. The team systematically screened PEGylated lipids to determine their impact on mRNA delivery efficiency, stability, and cellular uptake. Using advanced techniques such as Laurdan assays and small-angle X-ray scattering (SAXS), they identified optimal lipid compositions that enhance mRNA encapsulation and reduce immunogenicity. This work provides a framework for tailoring LNPs to specific therapeutic applications, particularly for vaccines and gene therapies.

University of Pennsylvania: Safer Plasmid DNA Delivery via Modified LNPs

Release Date: April 4, 2025

Website Link: https://www.bioanalysis-zone.com/breakthrough-in-dna-delivery-modified-lipid-nanoparticles-enable-safer-gene-expression/

Authors: Manthan N. Patel, Sachchidanand Tiwari et al.

Related Institution: Perelman School of Medicine, University of Pennsylvania (Philadelphia, PA, USA)

Researchers at the University of Pennsylvania developed a novel LNP formulation incorporating nitro-oleic acid (NOA), an anti-inflammatory lipid, to mitigate immune responses triggered by plasmid DNA (pDNA) delivery. By inhibiting the cGAS-STING pathway, NOA-pDNA-LNPs reduced inflammation in mice while achieving 11.5-fold higher transgene expression compared to mRNA-LNPs at 32 days post-administration. This breakthrough, published in Nature Biotechnology, addresses a critical barrier to DNA-based therapies for chronic diseases.

East China Normal University/YolTech Therapeutics: CRISPR-LNP Therapy for PH1

Dr. Yuxuan Wu and Dr. Emma Wang are part of a team of researchers who have developed a single-dose therapeutic genome editing approach using lipid nanoparticles for the treatment of primary hyperoxaluria type 1.

Release Date: April 7, 2025

Website Link: https://crisprmedicinenews.com/news/single-dose-therapeutic-genome-editing-using-lipid-nanoparticles-shows-promise-in-mouse-models-of-ra/

Authors: Yuxuan Wu, Emma Wang, et al.

Related Institutions: East China Normal University and YolTech Therapeutics (Shanghai, China)

A collaborative study demonstrated that a single intravenous dose of CRISPR-Cas9-loaded LNPs targeting the Hao1 gene reduced urinary oxalate levels by 75% in PH1 mouse models. The therapy, published in Molecular Therapy, sustained therapeutic effects for 12 months with minimal off-target activity. By avoiding viral vectors and leveraging liver-targeting LNPs, this approach offers a cost-effective solution for PH1, a rare metabolic disorder affecting children.

Icahn School of Medicine at Mount Sinai: Brain-Targeting mRNA LNPs

Release Date: April 7, 2025

Website Link: https://www.sciencedaily.com/releases/2025/02/250217133446.htm

Authors: Chang Wang, Yonger Xue et al.

Related Institution: Icahn School of Medicine at Mount Sinai (New York, NY, USA)

Mount Sinai researchers engineered LNPs capable of traversing the blood-brain barrier to deliver mRNA via intravenous injection. Tested in mice and human brain tissue, this platform enabled functional protein expression in neurons and glial cells, paving the way for treatments targeting Alzheimer’s disease, brain cancer, and addiction. The study, published in Nature Materials, highlights the potential of LNPs to revolutionize neurological drug delivery.

ACS Biochemistry Study: "Click Chemistry" LNPs for Targeted Delivery

LNP for the Delivery of mRNA to Metabolically Labeled Cancer Cells

Release Date: April 3, 2025 Website Link: https://pubs.acs.org/doi/abs/10.1021/acs.biochem.4c00699

Related Institution: University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States

A study in Biochemistry introduced LNPs functionalized with dibenzocyclooctyne (DBCO) lipids, which bind to azide-labeled cancer cells via bioorthogonal "click" chemistry. By metabolically labeling cells with azide groups, the DBCO-LNPs achieved selective mRNA delivery, with a 50-fold increase in expression compared to non-targeted LNPs. This approach, which avoids PEGylated lipids, enhances specificity for cancer therapy applications.

Conclusion

The first week of April 2025 marked significant progress in LNP technology, with advancements in lipid chemistry, DNA/RNA delivery, and targeted therapies. Innovations ranged from Sanofi’s PEGylated lipid optimizations to Mount Sinai’s brain-targeting LNPs, underscoring the versatility of lipid nanoparticles in addressing diverse medical challenges. These developments highlight the growing role of LNPs in enabling safer, more precise genetic medicines.