CD47 peptide-cloaked lipid nanoparticles promote cell-specific mRNA delivery

Mar 15, 2025Molecular therapy : the journal of the American Society of Gene Therapy

Lipid nanoparticles covered with CD47 peptide help deliver mRNA to specific cells

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

CD47 modification decreased macrophage and hepatic uptake of lipid nanoparticles by up to 3-fold.

Lipid nanoparticles modified with CD47 may reduce clearance by the immune system.
Combining CD47 modification with specific antibodies enhanced targeting efficiency for certain cell types.
Targeting hematopoietic stem cells with CD47/tLNP could facilitate targeted delivery of therapeutic mRNA.
CD47-modified lipid nanoparticles showed reduced inflammatory effects on liver tissue.
The CD47/tLNP-mRNA platform aims to improve the delivery and efficacy of mRNA therapeutics in vivo.

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mRNA-based therapeutics delivered via lipid nanoparticles (LNP-mRNA) hold great promise for treating diverse diseases. However, further improvements are needed to refine outcomes in non-vaccine, extrahepatic applications, such as minimizing the rapid clearance and off-target uptake in undesired tissues of the mononuclear phagocyte system (MPS). We propose modifying LNP surfaces with the phagocytic cell "don't eat me" signal, CD47, in combination with our previously established antibody-based targeted LNP (tLNP) to create a CD47/tLNP platform with reduced phagocytic clearance and off-target effects and improved efficiency for cell-specific delivery. We showed that CD47 modification decreased macrophage and hepatic uptake both in vitro and in vivo. Combining CD47 modification with antibodies targeting endothelial cells, T cells, or hematopoietic stem cells (HSCs) increased targeting efficiency up to 3-fold compared to tLNP alone. Enhanced targeting of CD47/tLNP to HSCs with reduced off-targeting enabled the delivery of pro-apoptotic mRNA for HSC depletion as a preconditioning strategy prior to bone marrow transplant. Additionally, CD47-modified LNPs showed diminished inflammatory effects on hepatic tissue and an altered protein corona. Our CD47/tLNP-mRNA platform, with its reduced phagocytic clearance, mitigated inflammatory effects, and enhanced targeted delivery, should further facilitate the development of in vivo mRNA therapeutics.

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CD47 peptide-cloaked lipid nanoparticles promote cell-specific mRNA delivery

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