Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 2;33(7):3195-3208.
doi: 10.1016/j.ymthe.2025.03.018. Epub 2025 Mar 13.

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

Tyler Ellis Papp  1 , Jianhao Zeng  1 , Hamna Shahnawaz  1 , Awurama Akyianu  1 , Laura Breda  2 , Amir Yadegari  1 , Joseph Steward  1 , Ruiqi Shi  3 , Qin Li  3 , Barbara L Mui  4 , Ying K Tam  4 , Drew Weissman  5 , Stefano Rivella  6 , Vladimir Shuvaev  1 , Vladimir R Muzykantov  7 , Hamideh Parhiz  8
Affiliations

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

Tyler Ellis Papp et al. Mol Ther. .

Abstract

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.

Keywords: CD47 modification; LNP; enhanced targeted delivery; lipid nanoparticle; mRNA delivery; “don’t eat me” signal.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests H.P. and D.W. are scientific founders and hold equity in Capstan Therapeutics. Y.K.T. is an employee of and holds equity in Acuitas Therapeutics. D.W. and H.P. receive research support from Capstan Therapeutics and BioNTech. H.P., D.W. V.R.M., and T.E.P. are inventors (University of Pennsylvania) on a patent describing some of the work presented here. These interests have been fully disclosed to the University of Pennsylvania.

References

    1. Rurik J.G., Tombácz I., Yadegari A., Méndez Fernández P.O., Shewale S.V., Li L., Kimura T., Soliman O.Y., Papp T.E., Tam Y.K., et al. CAR T cells produced in vivo to treat cardiac injury. Science (New York, N.Y.) 2022;375:91–96. doi: 10.1126/science.abm0594. - DOI - PMC - PubMed
    1. Tombácz I., Laczkó D., Shahnawaz H., Muramatsu H., Natesan A., Yadegari A., Papp T.E., Alameh M.-G., Shuvaev V., Mui B.L., et al. Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs. Mol. Ther. 2021;29:3293–3304. doi: 10.1016/j.ymthe.2021.06.004. - DOI - PMC - PubMed
    1. Breda L., Papp T.E., Triebwasser M.P., Yadegari A., Fedorky M.T., Tanaka N., Abdulmalik O., Pavani G., Wang Y., Grupp S.A., et al. In vivo hematopoietic stem cell modification by mRNA delivery. Science. 2023;381:436–443. doi: 10.1126/science.ade6967. - DOI - PMC - PubMed
    1. Kiaie S.H., Majidi Zolbanin N., Ahmadi A., Bagherifar R., Valizadeh H., Kashanchi F., Jafari R. Recent advances in mRNA-LNP therapeutics: immunological and pharmacological aspects. J. Nanobiotechnology. 2022;20:276. doi: 10.1186/s12951-022-01478-7. - DOI - PMC - PubMed
    1. Akinc A., Querbes W., De S., Qin J., Frank-Kamenetsky M., Jayaprakash K.N., Jayaraman M., Rajeev K.G., Cantley W.L., Dorkin J.R., et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. : J. Am. Soc. Gene Ther. 2010;18:1357–1364. - PMC - PubMed

LinkOut - more resources