Spherical nucleic acids with tailored and active protein coronae
Inventors
Mirkin, Chad A. • Zhang, Wuliang • Meckes, Brian R.
Assignees
Publication Number
US-12319711-B2
Publication Date
2025-06-03
Expiration Date
2040-09-18
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Abstract
The disclosure is generally related to spherical nucleic acids (SNAs) comprising a protein corona, wherein the SNA comprises (i) a nanoparticle core and (ii) one or more oligonucleotides attached to the surface of the nanoparticle core, wherein the protein corona comprises a plurality of proteins. The disclosure also provides methods of using the same. The disclosure further provides methods of improving stability and/or extending blood circulation half-life of a spherical nucleic acid (SNA), the SNA comprising a nanoparticle core and one or more oligonucleotides attached to the surface of the nanoparticle core, the method comprising adsorbing a plurality of proteins on the surface of the SNA.
Core Innovation
The invention relates to spherical nucleic acids (SNAs) with a tailored and active protein corona, wherein the SNA comprises a nanoparticle core and one or more oligonucleotides attached to the surface of the nanoparticle core. The innovation involves adsorbing a plurality of proteins onto the SNA surface via non-covalent interactions, resulting in a protein corona containing at least five proteins. These proteins may include targeting proteins, dysopsonins, complement inhibitors, or combinations thereof, imparting additional functionality to the SNAs.
The problem addressed is that, when nanomaterials like SNAs enter biological fluids, they non-specifically adsorb biomolecules and form protein coronae. This protein corona alters blood circulation time, biodistribution, and targeting efficiency, which can diminish therapeutic potential. Traditional attempts, such as PEGylation or antibody-DNA conjugation, have limitations, such as reduced uptake efficiency or low antibody densities that do not significantly affect the protein corona.
By deliberately designing and adsorbing functional proteins onto the SNA surface, the invention enables control over the protein corona, improving stability and/or extending blood circulation half-life. The method retains or enhances the targeting ability of SNAs, reduces nonspecific uptake by the mononuclear phagocyte system, and ensures that the oligonucleotide shell remains functional and accessible even in biological fluids. The approach is easy and flexible, accommodating various active proteins for tailored biological properties depending on the intended application.
Claims Coverage
There are two independent claims in the patent. Each independent claim defines core inventive features directed to SNAs with tailored protein coronae and related methods or compositions.
Spherical nucleic acid with non-covalently adsorbed protein corona
A spherical nucleic acid (SNA) comprising: - A nanoparticle core; - One or more oligonucleotides attached to the surface of the nanoparticle core; - A protein corona comprising a plurality of proteins, each of which is adsorbed onto the surface of the SNA via non-covalent interaction; - The plurality of proteins comprises at least five proteins.
Plurality of monodisperse SNAs with protein corona and specified core types
A plurality of spherical nucleic acids (SNAs), each comprising: - A nanoparticle core selected from metallic, micellar, liposomal, polymer, metal-organic framework, or combinations thereof; - One or more oligonucleotides attached to the surface; - A protein corona containing a plurality of proteins (at least five) adsorbed by non-covalent interaction on each SNA; - The plurality of SNAs is monodisperse.
The claims broadly protect SNAs with a specified number and type of adsorbed functional proteins, specifying non-covalent adsorption, coverage of multiple nanoparticle core types, and monodispersity in SNA populations.
Stated Advantages
Provides an easy and flexible approach to SNA modification for cellular selectivity.
The pre-adsorbed protein corona remains functional in the presence of serum.
The pre-adsorbed protein corona protects oligonucleotides on the nanoparticle surface from rapid digestion by endonucleases.
Oligonucleotides on the SNAs remain accessible even with the protein corona present.
Imparts cellular selectivity to SNAs and reduces nonspecific macrophage clearance without interfering with oligonucleotide shell performance.
Can improve SNA targeting capabilities and extend blood circulation half-life.
Documented Applications
Structures can be used to render targeting capabilities for selected cell populations.
Creation of active protein coronae for improving the biological properties of SNAs.
Gene silencing using SNAs with tailored protein coronae.
Immunomodulation with SNAs pre-adsorbed with functional proteins.
Drug delivery through protein-adsorbed SNAs.
mRNA detection in live cells using designed SNAs.
Selective targeting of cancer cells, such as HER2-positive breast cancer cells, with antibody-adsorbed SNAs.
Reduction of macrophage uptake for extended blood circulation half-life of SNAs.
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