Synthetic nucleic acids and methods of using the same for improved polypeptide production

Abstract

This disclosure relates to synthetic nucleic acid molecules, such as synthetic mRNA molecules, containing chemical modifications that improve nucleic acid stability while simultaneously preserving the ability of the nucleic acid to be processed by endogenous translational machinery and to furnish protein product.

Description

[0001]PATENT ATTORNEY DOCKET NO.50858-153WO4 SYNTHETIC NUCLEIC ACIDS AND METHODS OF USING THE SAME FOR IMPROVED POLYPEPTIDE PRODUCTION SEQUENCE LISTING The present application is being filed with a Sequence Listing in XML format. The Sequence Listing File, entitled 50858-153WO4_Sequence_Listing_2_13_25.xml, was created on February 13, 2025, and is 84,952 bytes in size. The information in electronic format of the sequence listing is incorporated herein by reference in its entirety. BACKGROUND The use of exogenous nucleic acids (e.g., ribonucleic acids, such as mRNA) has become a particularly effective strategy for delivering polypeptides of interest to a target cell, tissue, or organism, as a single protein-encoding nucleic acid can be translated to yield multiple copies of a desired polypeptide, allowing the administration of a small quantity of nucleic acid to achieve high levels of protein expression. As the nucleic acid therapeutic field has grown, steps have been taken to improve the pharmacokinetic properties of nucleic acid molecules. For example, efforts to further augment the half-lives of nucleic acid molecules, such as protein-encoding mRNA molecules, have led to modifications that render nucleic acids less susceptible to enzymatic or chemical degradation. Although such modifications may promote nucleic acid stability, many of these modifications are not tolerated by the endogenous nucleic acid translation machinery – particularly, by the ribosome. Accordingly, although certain modifications may be useful for reducing nucleolytic cleavage or slowing chemically induced decomposition, many such modifications are incapable of promoting the production of useful protein product. There remains a need for improved strategies for increasing nucleic acid half-life, while simultaneously preserving the ability of the nucleic acid to be translated into a functional protein output. SUMMARY The disclosure provides polypeptide-encoding nucleic acid molecules, such as RNA molecules (e.g., mRNA molecules), that contain synthetic chemical modifications. These nucleic acid molecules are termed herein “synRNA” molecules. The synRNA molecules described herein provide the unexpected benefit of not only exhibiting improved nucleic acid half-life relative to their unmodified counterparts, but do so while simultaneously preserving the ability of the nucleic acid to be translated by the ribosome so as to yield polypeptide product. In a first aspect, the disclosure features a synthetic RNA molecule (synRNA) containing, in the 5’- to-3’ direction: a) a 5’ cap structure; b) a 5’ untranslated region (UTR); c) an open reading frame (ORF) encoding a polypeptide; d) a 3’ UTR; and e) a poly-A region; wherein the synRNA comprises one or more, or all, of the following features: i) a modified internucleoside linkage in the ORF; ii) a modified internucleoside linkage in the 5’ or 3’ UTR; iii) a modified internucleoside linkage in the poly-A region; iv) a 2’ modified ribose in the ORF; v) a 2’ modified ribose in the 5’ or 3’ UTR; or vi) a 2’ modified ribose in the poly-A region. PATENT ATTORNEY DOCKET NO.50858-153WO4 In a further aspect, the disclosure features a synRNA containing , in the 5’-to-3’ direction: a) optionally, a 5’ cap structure; b) optionally, a 5’ UTR; c) an ORF encoding a polypeptide; d) optionally, a 3’ UTR; and e) optionally, a poly-A region; wherein the ORF comprises at least one codon of Formula SYN-I: -L1-B1-L2-B2-L3-B3-L4- (SYN-I) wherein: each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; each of B1and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside; B2is an unmodified nucleoside, a 2’ modified nucleoside, or a nucleobase-modified nucleoside; and (i) at least one of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) at least one of B1and B3is a 2’ modified nucleoside, or (iii) B2is a 2’ modified nucleoside or a nucleobase-modified nucleoside; further wherein: when B1is a 2’ modified nucleoside, (i) at least one of B2and B3is a modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B2is a 2’ modified nucleoside, (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B2is a nucleobase-modified nucleoside, (i) B1and B3are unmodified nucleosides, or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B3is a 2’ modified nucleoside, (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; and when one or more of L1, L2, L3, and L4is a modified internucleoside linkage, (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, (iv) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside, or (v) the modified internucleoside linkage is . In some embodiments of Formula SYN-I: each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; each of B1, B2, and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside; and (i) at least one of L1, L2, L3, and L4is a modified internucleoside linkage or (ii) at least one of B1, B2, and B3is a 2’ modified nucleoside; further wherein: when B1is a 2’ modified nucleoside, (i) at least one of B2and B3is a modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; PATENT ATTORNEY DOCKET NO.50858-153WO4 when B2is a 2’ modified nucleoside, (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B3is a 2’ modified nucleoside, (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; and when one or more of L1, L2, L3, and L4is a modified internucleoside linkage, (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, (iv) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside, or (v) the modified internucleoside linkage is .. In some embodiments, B1is a 2’ modified nucleoside, and (i) at least one of B2and B3is a 2’ modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, B2is a 2’ modified nucleoside, and (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, B3is a 2’ modified nucleoside, and (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, L1, L2, L3, or L4is a modified internucleoside linkage, and (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, or (iv) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, the synRNA comprises a 2’ modified nucleoside in the 5’ UTR. For example, each nucleoside in the 5’ UTR may be a 2’ modified nucleoside. In some embodiments, the synRNA comprises a 2’ modified nucleoside in the 3’ UTR. For example, each nucleoside in the 3’ UTR may be a 2’ modified nucleoside. In some embodiments, the synRNA comprises a 2’ modified nucleoside in the poly-A region. For example, each nucleoside in the poly-A region may be a 2’ modified nucleoside. In some embodiments, the 2’ modified nucleoside in the 5’ UTR is a 2’-methoxy nucleoside. In some embodiments, the 5’ UTR comprises at least one 2’-methoxy nucleoside. In some embodiments, the 5’ UTR comprises at least 10% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 20% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 30% 2’- methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 40% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 50% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 60% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 70% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 80% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises at least 90% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR comprises 100% 2’-methoxy nucleosides. In some embodiments, the 2’ modified nucleoside in the 3’ UTR is a 2’-methoxy nucleoside. In some embodiments, the 3’ UTR comprises at least one 2’-methoxy nucleoside. In some embodiments, PATENT ATTORNEY DOCKET NO.50858-153WO4 the 3’ UTR comprises at least 10% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 20% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 30% 2’- methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 40% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 50% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 60% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 70% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 80% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises at least 90% 2’-methoxy nucleosides. In some embodiments, the 3’ UTR comprises 100% 2’-methoxy nucleosides. In some embodiments, the 2’ modified nucleoside in the poly-A tail is a 2’-methoxy nucleoside. In some embodiments, the poly-A tail comprises at least one 2’-methoxy nucleoside. In some embodiments, the poly-A tail comprises at least 10% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 20% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 30% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 40% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 50% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 60% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 70% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 80% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises at least 90% 2’-methoxy nucleosides. In some embodiments, the poly-A tail comprises 100% 2’-methoxy nucleosides. In some embodiments, the 2’ modified nucleoside in the 5’ UTR, the 3’ UTR, and / or the poly-A tail is a 2’-methoxy nucleoside. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least one 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 10% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 20% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 30% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 40% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 50% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 60% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 70% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 80% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise at least 90% 2’-methoxy nucleosides. In some embodiments, the 5’ UTR, 3’ UTR, and poly-A tail all comprise 100% 2’-methoxy nucleosides. In some embodiments, the synRNA comprises a modified internucleoside linkage in the 5’ UTR. For example, each internucleoside linkage in the 5’ UTR may be a modified internucleoside linkage. In some embodiments, the synRNA comprises a modified internucleoside linkage in the 3’ UTR. For example, each internucleoside linkage in the 3’ UTR may be a modified internucleoside linkage. In some embodiments, the synRNA comprises a modified internucleoside linkage in the poly-A region. For example, each internucleoside linkage in the poly-A region may be a modified internucleoside linkage. In some embodiments, each modified internucleoside linkage is, independently, selected from the group consisting of a phosphorothioate, a phosphoroselenate, a boranophosphate, a boranophosphate ester, a hydrogen phosphonate, a phosphoramidate, a phosphorodiamidate, an alkyl phosphonate, an PATENT ATTORNEY DOCKET NO.50858-153WO4 aryl phosphonate, a phosphotriester, a phosphorodithioate, a bridged phosphoramidate, a bridged phosphorothioate, a bridged methylene-phosphonate, and an α-thio phosphate. In some embodiments, each modified internucleoside linkage is a phosphorothioate internucleoside linkage. In some embodiments, one or more of the modified internucleoside linkages comprises the structure: . In some embodiments, each 2’ modified nucleoside is, independently, a nucleoside comprising a 2’ ribose modification selected from the group consisting of a 2’-deoxyribose, a 2’-OMe ribose, a 2’-O- methoxyethyl ribose (2’-MOE), a 2’-F ribose, a 2’-NH2 ribose, a 2’fluoroarabino ribose (FANA), a locked nucleic acid (LNA), and a 4’-S ribose. In some embodiments, the 2’ ribose modification is a 2’-O-methyl ribose or a 2’-fluoro ribose. In some embodiments, the poly-A region is bound, at its 3’ end, to a modified nucleoside. In some embodiments, the modified nucleoside bound to the poly-A region is selected from the group consisting of an inverted deoxythymidine, a 2’-deoxynucleoside, a 3’-deoxynucleoside, a 2’,3’-dideoxynucleoside, a 2’- O-methylnucleoside, a 3’-O-methylnucleoside, a 3’-O-ethyl-nucleoside, 3’-arabinoside, an L-nucleoside, an alpha-thio-2’-O-methyl-adenosine, 2’-fluoro-adenosine, an arabino-adenosine, a hexitol-adenosine, an LNA-adenosine, a PNA-adenosine, and a 3’-azido-2´,3´-dideoxyadenosine. In some embodiments, the modified nucleoside is an inverted deoxythymidine. In some embodiments, the codon of SYN-I has the structure of Formula SYN-II: -L1-B1-L2-B2-L3-B3-L4- wherein: each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage, optionally wherein the modified internucleoside linkage is selected from the group consisting of a phosphorothioate, a phosphoroselenate, a boranophosphate, a boranophosphate ester, a hydrogen phosphonate, a phosphoramidate, a phosphorodiamidate, an alkyl phosphonate, an aryl phosphonate, a phosphotriester, a phosphorodithioate, a bridged phosphoramidate, a bridged phosphorothioate, a bridged methylene-phosphonate, and an α-thio phosphate; each of B1, B2, and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside; and at least one of B1, B2, and B3is a 2’ modified nucleoside, optionally wherein the 2’ modified nucleoside comprises a 2’ ribose modification selected from the group consisting of a 2’-deoxyribose, a 2’-OMe ribose, a 2’-MOE, a 2’-F ribose, a 2’-NH2 ribose, a 2’FANA, an LNA, and a 4’-S ribose. In some embodiments of Formula SYN-II, B1is a 2’-modified nucleoside. In some embodiments, B1is a 2’-fluoro nucleoside. In some embodiments, B1is an LNA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-III: -L1-F-L2-B2-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; PATENT ATTORNEY DOCKET NO.50858-153WO4 each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B2and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-IV: -L1-B1-L2-B2-L3-F-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-V: -L1-F-L2-B2-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; B2is an unmodified nucleoside; and B3is a 2’ modified nucleoside. In some embodiments, B3is a 2’-fluoro nucleoside. In some embodiments, B3is an LNA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-VI: -S-B1-L2-B2-L3-B3-S- wherein: S is a phosphorothioate internucleoside linkage; each of L2and L3is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1, B2, and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-VII: -S-B1-L2-B2-L3- B3-S- wherein: S is a phosphorothioate internucleoside linkage; each of L2and L3is an unmodified internucleoside linkage; and one or more of B1, B2, and B3is an unmodified nucleoside (e.g., wherein each of B1, B2, and B3is an unmodified nucleoside). In some embodiments, the codon of SYN-I has the structure of Formula SYN-VIII: -L1-B1-L2-B2-L3-R-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and R is an arabinose nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-IX: -L1-N-L2-B2-L3-B3-L4- wherein: N is an LNA nucleoside; PATENT ATTORNEY DOCKET NO.50858-153WO4 each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B2and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-X: -L1-N-L2-B2-L3-B3-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B2and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XI: -L1-B1-L2-F-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XII: -L1-B1-L2-F-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XIII: -L1-B1-L2-N-L3-B3-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1and B3is, independently, an unmodified nucleoside or a modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XIV: -L1-B1-L2-N-L3-B3-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XV: -L1-B1-L2-B2-L3-N-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and PATENT ATTORNEY DOCKET NO.50858-153WO4 each of B1and B2is, independently, an unmodified nucleoside or a modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XVI: -L1-B1-L2-B2-L3-N-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XVII: -L1-B1-L2-B2-L3-M-L4- wherein: M is a 2’-methoxy nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XVIII: -L1-B1-S-B2-L3- B3-L4- wherein: S is a phosphorothioate internucleoside linkage; each of L1, L3and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XIX: -L1-B1-L2-B2-S- B3-L4- wherein: S is a phosphorothioate internucleoside linkage; each of L1, L2and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XX: -S-B1-L2-F-L3-B3-S- wherein: S is a phosphorothioate internucleoside linkage; F is a 2’-fluoro nucleoside; each of L2and L3is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXI: -S-B1-L2-F-L3-B3-S- wherein: S is a phosphorothioate internucleoside linkage; F is a 2’-fluoro nucleoside; each of L2and L3is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXII: PATENT ATTORNEY DOCKET NO.50858-153WO4 -L1-B1-L2-B2-S-M-L4- wherein: M is a 2’-methoxy nucleoside; S is a phosphorothioate internucleoside linkage; each of L1, L2, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXIII: -L1-B1-L2-B2-L3-M-S- wherein: each of L1, L2, and L3is a phosphodiester internucleoside linkage; S is a phosphorothioate internucleoside linkage; each of B1and B2is an unmodified nucleoside; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXIV: -L1-B1-L2-B2-L3-B3-Z- wherein: each of L1, L2, and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure: . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXV: -L1-B1-Z-B2-L3-B3-L4- wherein: each of L1, L3, and L4is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure: . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXVI: -L1-B1-Z-B2-L3-B3-Z- wherein: each of L1and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure: PATENT ATTORNEY DOCKET NO.50858-153WO4 . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXVII: -L1-F-L2-B2-L3-M-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; B2is an unmodified nucleoside; M is a 2’-methoxy nucleoside; and F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXVIII: -L1-M-L2-M-L3-M-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXIX: -S-M-S-M-S-M-L4- wherein: L4is a phosphodiester internucleoside linkage; S is a phosphorothioate internucleoside linkage; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXX: -L1-M-L2-B2-L3-B3-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B2and B3is an unmodified nucleoside; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXI: -L1-B1-L2-M-L3-B3-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B1and B3is an unmodified nucleoside; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXII: -L1-B1-L2-B2-L3-D-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and D is a deoxyribonucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXIII: PATENT ATTORNEY DOCKET NO.50858-153WO4 -L1-D-L2-D-L3-D-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; and D is a deoxyribonucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXIV: -L1-B1-L2-m6A-L3-B3-L4- wherein: m6A is N6-methyl-adenosine; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXV: -L1-F-L2-B2-S-B3-L4- wherein: each of L1, L2, and L4are phosphorothioate internucleoside linkages; each of B2and B3is an unmodified nucleoside; and F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXVI: -S-F-L2-B2-L3-B3-S- wherein: each of L2and L3are phosphorothioate internucleoside linkages; S is a phosphorothioate internucleoside linkage; each of B2and B3is an unmodified nucleoside; and F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXVII: -S-B1-L2-B2-L3-F-S- wherein: each of L2and L3are phosphorothioate internucleoside linkages; S is a phosphorothioate internucleoside linkage; each of B1and B2is an unmodified nucleoside; and F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXVIII: -S-F-L2-F-L3-B3-S- wherein: each of L2and L3are phosphorothioate internucleoside linkages; S is a phosphorothioate internucleoside linkage; B3is an unmodified nucleoside; and each F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXIX: PATENT ATTORNEY DOCKET NO.50858-153WO4 -L1-FN-L2-B2-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B2and B3is an unmodified nucleoside; and FN is a 2’-FANA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XL: -L1-B1-L2-FN-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B3is an unmodified nucleoside; and FN is a 2’-FANA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLI: -L1-B1-L2- B2-L3-FN-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and FN is a 2’-FANA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLII: -L1-N-L2-B2-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B2and B3is an unmodified nucleoside; and N is a 2’-NH2 nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLIII: -L1-B1-L2-N-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B3is an unmodified nucleoside; and N is a 2’-NH2 nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLIV: -L1-B1-L2- B2-L3-N-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and N is a 2’- NH2 nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLV: -L1-B1-L2-B2-Q-B3-L4- wherein: each of L1, L2and L3is a phosphodiester internucleoside linkage; PATENT ATTORNEY DOCKET NO.50858-153WO4 each of B1, B2, and B3is an unmodified nucleoside; and Q represents a modified internucleoside linkage of the following structure: . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLVI: -L1-B1-L2-B2-L3-B3-Q- wherein: each of L1, L2, and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Q represents a modified internucleoside linkage of the following structure: . In some embodiments, only one codon in the synRNA has the structure of SYN-I. Alternatively, in some embodiments, the synRNA comprises a plurality of codons having the structure of SYN-I. For example, the synRNA may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or more codons having the structure of SYN-I. In some embodiments, fewer than 1% of the codons in the synRNA have the structure of SYN-I. Alternatively, in some embodiments, between 2% and 100% of the codons in the synRNA have the structure of SYN-I. For example, in some embodiments, at least 2% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 3% of the codons in the synRNA have the structure of SYN-I. In some embodiments, In some embodiments, at least 4% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 5% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 6% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 7% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 8% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 9% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 10% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 20% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 30% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 40% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 50% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 60% of the codons in the synRNA have the structure of SYN-I. In some PATENT ATTORNEY DOCKET NO.50858-153WO4 embodiments, at least 70% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 80% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 90% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 91% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 92% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 93% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 94% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 95% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 96% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 97% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 98% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 99% of the codons in the synRNA have the structure of SYN-I. In some embodiments, 100% of the codons in the synRNA have the structure of SYN-I. In some embodiments, the synRNA comprises two consecutive codons that, together, have the structure of Formula SYN-XLVII: -S-F-L2-F-L3-B3-S-B4-L5-F-L6-B6-S- wherein: each S is a phosphorothioate internucleoside linkage; each F is a 2’-fluoro nucleoside; each of L2, L3, L5, and L6is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B3, B4, and B6is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments of Formula SYN-XLVII: each S is a phosphorothioate internucleoside linkage; each of L2, L3, L5, and L6is an unmodified internucleoside linkage; and each of B3, B4, and B6is an unmodified nucleoside. In some embodiments, the synRNA comprises two consecutive codons that, together, have the structure of Formula SYN-XLVIII: -S-F-L2-F-L3-B3-S-F-L5-B5-L6-B6-S wherein: each S is a phosphorothioate internucleoside linkage; each F is a 2’-fluoro nucleoside; each of L2, L3, L5, and L6is an unmodified internucleoside linkage; and each of B3, B5, and B6is an unmodified nucleoside. In some embodiments, the synRNA comprises two consecutive codons that, together, have the structure of Formula SYN-XLIX: -S-F-L2-B2-L3-F-S-B4-L5-F-L6-B6-S wherein: each S is a phosphorothioate internucleoside linkage; each F is a 2’-fluoro nucleoside; each of L2, L3, L5, and L6is an unmodified internucleoside linkage; and PATENT ATTORNEY DOCKET NO.50858-153WO4 each of B2, B4, and B6is an unmodified nucleoside. In some embodiments, the disclosure provides a synRNA containing, in the 5’ to 3’ direction: a) a 5’ cap structure; b) a 5’ UTR consisting of 2’-methoxy nucleosides; c) an ORF encoding a polypeptide that does not comprise a 2’-modification or a modified internucleoside linkage; d) a 3’ UTR consisting of 2’-methoxy nucleosides; and e) a poly-A region consisting of 2’-methoxy nucleosides. In some embodiments, the disclosure provides a synRNA containing, in the 5’ to 3’ direction: a) a 5’ cap structure; b) a 5’ UTR having all 2’-methoxy nucleosides; c) an ORF encoding a polypeptide, wherein all codons in the ORF have the structure of Formula SYN-III; d) a 3’ UTR having all 2’-methoxy nucleosides; and e) a poly-A region having all 2’-methoxy nucleosides. In some embodiments, the disclosure provides a synRNA containing, in the 5’ to 3’ direction a) a 5’ cap structure; b) a 5’ UTR having all 2’-methoxy nucleosides; c) an ORF encoding a polypeptide, wherein all codons in the ORF have the structure of Formula SYN-XXXV; d) a 3’ UTR having all 2’-methoxy nucleosides; and e) a poly-A region having all 2’-methoxy nucleosides. In some embodiments of any of the foregoing aspects or embodiments of the disclosure, one or more of the nucleosides in the ORF comprise a nucleobase modification. In some embodiments, one or more of the 2’ modified nucleosides in the ORF further comprise a nucleobase modification. In some embodiments, the nucleobase modification is N1-methyl-pseudouracil. In some embodiments, one or more uracil nucleobases in the ORF comprise the N1-methyl- pseudouracil nucleobase modification. In some embodiments, each uracil nucleobase in the ORF comprises the N1-methyl-pseudouracil nucleobase modification. In some embodiments, the synRNA is from 25 to 500 nucleotides in length (e.g., 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 nucleotides in length). In some embodiments, the synRNA is from 50 to 150 nucleotides in length (e.g., 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 nucleotides in length). In some embodiments, the 3’UTR and the poly-A region are joined by way of a linker. In some embodiments, the 5’ or 3’ UTR contains a linker, such as an ethylene glycol linker. In some embodiments, the 5’ or 3’ UTR contains a monoethylene glycol linker, a diethylene glycol linker, a triethylene glycol linker, or a tetraethylene glycol linker. In some embodiments, the synRNA of any of the foregoing aspects or embodiments of the disclosure exhibits increased expression compared to a corresponding unmodified RNA molecule when introduced into a cell or a population of cells. In some embodiments, the maximum expression of the synRNA is increased compared to the maximum expression of a corresponding unmodified RNA. In some PATENT ATTORNEY DOCKET NO.50858-153WO4 embodiments, the total expression over a period of time (e.g., 24 hours, 48 hours, 72 hours, or 96 hours) of the synRNA is increased compared to the total expression of a corresponding unmodified RNA over the same period of time. In some embodiments, the synRNA of any of the foregoing aspects or embodiments of the disclosure exhibits increased stability compared to a corresponding unmodified RNA molecule when introduced into a cell or a population of cells. In some embodiments the synRNA exhibits increased stability over a period of time (e.g., 24 hours, 48 hours, 72 hours, 96 hours, or more) compared to a corresponding unmodified RNA. In some embodiments, the increased stability can manifest as expression that is prolonged relative to a corresponding unmodified RNA molecule (e.g., prolonged by at least 1 hour, at least 2 hours, at least 3 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or longer). In some embodiments, the increased expression and / or improved stability is attributable to the modification of the 5'UTR, 3'UTR, poly-A tail, ORF, or a combination thereof. In a further aspect, the disclosure features a method of increasing the stability or expression of a polypeptide-encoding RNA. The method includes designing an ORF encoding the polypeptide and incorporating the ORF into the synRNA of any of the foregoing aspects or embodiments of the disclosure. In some embodiments, the maximum expression of the synRNA is increased compared to the maximum expression of a corresponding unmodified RNA. In some embodiments, the total expression over a period of time (e.g., 24 hours, 48 hours, 72 hours, 96 hours, or more) of the synRNA is increased compared to the total expression of a corresponding unmodified RNA over the same period of time. In some embodiments, the increased expression and / or improved stability is attributable to the modification of the ORF. In another aspect, the disclosure features a method of expressing a polypeptide of interest in a subject (e.g., a mammalian subject, such as a human). The method includes administering to the subject the synRNA of any of the foregoing aspects or embodiments of the disclosure, wherein the ORF encodes the polypeptide of interest. In an additional aspect, the disclosure features a method of expressing a polypeptide of interest in a cell or population of cells (e.g., a population of mammalian cells, such as human cells). The method includes providing to the cell or population of cells the synRNA of any of the foregoing aspects or embodiments of the disclosure, wherein the ORF encodes the polypeptide of interest. In another aspect, the disclosure features a method of treating a disease or condition in a subject (e.g., a mammalian subject, such as a human) associated with a deficiency in an endogenous polypeptide. The method includes administering to the subject the synRNA of any of the foregoing aspects or embodiments of the disclosure, wherein the polypeptide encoded by the ORF corresponds to the polypeptide whose deficiency is associated with the disease or condition. In another aspect, the disclosure features a method of treating cancer in a subject (e.g., a mammalian subject, such as a human)in need thereof. The method includes administering to the subject the synRNA of any of the foregoing aspects or embodiments of the disclosure, wherein the polypeptide encoded by the ORF corresponds to an antigen expressed by one or more cells of said cancer. In another aspect, the disclosure features a method of expressing a cancer antigen in a subject (e.g., a mammalian subject, such as a human) diagnosed as having cancer. The method includes PATENT ATTORNEY DOCKET NO.50858-153WO4 administering to the subject the synRNA of any of the foregoing aspects or embodiments of the disclosure, wherein the polypeptide encoded by the ORF corresponds to an antigen expressed by one or more cells of said cancer. In a further aspect, the disclosure features a method of prophylactically treating a subject (e.g., a mammalian subject, such as a human) at risk of developing a disease. The method includes administering to the subject the synRNA of any of the foregoing aspects or embodiments of the disclosure, wherein the polypeptide encoded by the ORF corresponds to an antigen associated with said disease. In another aspect, the disclosure provides the synRNA of any of the above aspects or embodiments of the invention, wherein the polypeptide is alpha-1 type I collagen (COL1A1) or a functional fragment thereof. In some embodiments, the ORF encodes a COL1A1 polypeptide having an amino acid sequence that is at least 70% identical (e.g., at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to the amino acid sequence of NCBI Reference Sequence: NP_000079.2, the disclosure of which is incorporated herein by reference. In some embodiments, the ORF encodes a functional COL1A1 fragment having an amino acid sequence that is at least 70% identical (e.g., at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to a fragment of equal length within the amino acid sequence of NCBI Reference Sequence: NP_000079.2. In some embodiments, the ORF encodes a functional COL1A1 fragment having a length of at least 10 amino acids, at least 20 amino acids, at least 30 amino acids, at least 40 amino acids, at least 50 amino acids, at least 60 amino acids, at least 70 amino acids, at least 80 amino acids, at least 90 amino acids, at least 100 amino acids, at least 110 amino acids, at least 120 amino acids, at least 130 amino acids, at least 140 amino acids, at least 150 amino acids, at least 160 amino acids, at least 170 amino acids, at least 180 amino acids, at least 190 amino acids, at least 200 amino acids, at least 200 amino acids, at least 300 amino acids, at least 400 amino acids, at least 500 amino acids, at least 600 amino acids, at least 700 amino acids, at least 800 amino acids, at least 900 amino acids, at least 1,000 amino acids, at least 1,100 amino acids, at least 1,200 amino acids, at least 1,300 amino acids, at least 1,400 amino acids, or more. In some embodiments, the ORF encodes a functional COL1A1 fragment having a length of from 10 to 1,000 amino acids, from 10 to 900 amino acids, from 10 to 800 amino acids, from 10 to 700 amino acids, from 10 to 600 amino acids, from 10 to 500 amino acids, from 10 to 400 amino acids, from 10 to 300 amino acids, from 10 to 200 amino acids, from 10 to 100 amino acids, from 10 to 90 amino acids, from 10 to 80 amino acids, from 10 to 70 amino acids, from 10 to 60 amino acids, from 10 to 50 amino acids, from 10 to 40 amino acids, from 10 to 30 amino acids, or from 10 to 20 amino acids. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the ORF encodes a functional COL1A1 fragment having a length of from 20 amino acids to 200 amino acids, from 25 amino acids to 100 amino acids, from 30 amino acids to 75 amino acids, or from 35 to 50 amino acids. In some embodiments, the ORF encodes a functional COL1A1 fragment having a length of 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 amino acids, 32 amino acids, 33 amino acids, 34 amino acids, 35 amino acids, 36 amino acids, 37 amino acids, 38 amino acids, 39 amino acids, 40 amino acids, 41 amino acids, 42 amino acids, 43 amino acids, 44 amino acids, 45 amino acids, 46 amino acids, 47 amino acids, 48 amino acids, 49 amino acids, 50 amino acids, 51 amino acids, 52 amino acids, 53 amino acids, 54 amino acids, 55 amino acids, 56 amino acids, 57 amino acids, 58 amino acids, 59 amino acids, 60 amino acids, 61 amino acids, 62 amino acids, 63 amino acids, 64 amino acids, 65 amino acids, 66 amino acids, 67 amino acids, 68 amino acids, 69 amino acids, 70 amino acids, 71 amino acids, 72 amino acids, 73 amino acids, 74 amino acids, 75 amino acids, 76 amino acids, 77 amino acids, 78 amino acids, 79 amino acids, 80 amino acids, 81 amino acids, 82 amino acids, 83 amino acids, 84 amino acids, 85 amino acids, 86 amino acids, 87 amino acids, 88 amino acids, 89 amino acids, 90 amino acids, 91 amino acids, 92 amino acids, 93 amino acids, 94 amino acids, 95 amino acids, 96 amino acids, 97 amino acids, 98 amino acids, 99 amino acids, or 100 amino acids. In yet another aspect, the disclosure features a method of expressing exogenous COL1A1 in a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA of the foregoing aspect. In a further aspect, the disclosure features a method of replacing dermal collagen in a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA. In still another aspect, the disclosure features a method of reducing or preventing dermal atrophy in a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA. In a further aspect, the disclosure features a method of reducing or preventing wrinkle formation in a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA. In another aspect, the disclosure features a method of maintaining or improving skin strength in a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA. In a further aspect, the disclosure features a method of maintaining or improving skin firmness in a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA. In another aspect, the disclosure features a method of maintaining or improving skin elasticity in a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA. In a further aspect, the disclosure features a method of reducing or preventing one or more visual manifestations of aging in the skin of a subject by administering to the subject the COL1A1-encoding (or COL1A1 fragment-encoding) synRNA. In some embodiments, the one or more visual manifestations of aging are selected from the group consisting of skin wrinkling, skin spotting, a reduction in skin elasticity, a reduction in skin firmness, and a reduction in skin strength. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments of any of the foregoing methods, the subject is a human. In some embodiments, prior to the administering, the subject’s skin exhibits one or more visual manifestations of aging, such as skin wrinkling, skin spotting, a reduction in skin elasticity relative to the subject’s skin elasticity at a younger age, a reduction in skin firmness relative to the subject’s skin firmness at a younger age, or a reduction in skin strength relative to the subject’s skin strength at a younger age. In some embodiments, prior to the administering, the subject’s skin has undergone photoaging. In some embodiments, the synRNA is administered to the subject by way of any route of administration described herein, such as by way of intradermal, subcutaneous, intravenous, or intramuscular administration. In some embodiments, the synRNA is administered to the subject by way of one or more dermal patches. In an additional aspect, the disclosure features a host cell containing the synRNA of any of the foregoing aspects or embodiments of the disclosure. In some embodiments, the host cell is a eukaryotic cell, such as a mammalian cell (e.g., a human cell). In some embodiments, the host cell is a prokaryotic cell. In another aspect, the disclosure features a kit containing the synRNA of any of the foregoing aspects or embodiments, along with a package insert. In some embodiments, the package insert instructs a user of the kit to perform the method of any of the preceding aspects or embodiments of the disclosure. DEFINITIONS In order that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. In this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. The terms “a” (or “an”), as well as the terms “one or more,” and “at least one” can be used interchangeably herein. In certain aspects, the term “a” or “an” means “single.” In other aspects, the term “a” or “an” includes “two or more” or “multiple.” Furthermore, “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show,2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology,3rd ed., 1999, Academic Press; and the Oxford PATENT ATTORNEY DOCKET NO.50858-153WO4 Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. Wherever aspects are described herein with the language “comprising,” otherwise analogous aspects described in terms of “consisting of” and / or “consisting essentially of” are also provided. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is recited, it is to be understood that each intervening integer value, and each fraction thereof, between the recited upper and lower limits of that range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range where either, neither or both limits are included is also encompassed within the invention. Where a value is explicitly recited, it is to be understood that values which are about the same quantity or amount as the recited value are also within the scope of the present disclosure. Where a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is within the scope of the present disclosure. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having a plurality of alternatives, examples of that invention in which each alternative is excluded singly or in any combination with the other alternatives are also hereby disclosed; more than one element of an invention can have such exclusions, and all combinations of elements having such exclusions are hereby disclosed. As used herein, the term “about” refers to a value that is no more than 10% above or below the value being described. For example, the term “about 5 nM” indicates a range of from 4.5 nM to 5.5 nM. As used herein, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system. As used herein, the term “biodegradable” means capable of being broken down into innocuous products by the action of living things. As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a biological system and / or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular embodiments, a polynucleotide of the present disclosure can be considered biologically active if even a portion of the polynucleotide is biologically active or mimics an activity considered biologically relevant. As used herein, the term “amino acid substitution” refers to the replacement of an amino acid residue present in a parent or reference polypeptide (e.g., a target polypeptide described herein) with another amino acid residue. An amino acid can be substituted in a parent or reference sequence, for example, via chemical peptide synthesis or through recombinant methods known in the art. Accordingly, a reference to a “substitution at position X” refers to the substitution of an amino acid present at position X with an alternative amino acid residue. In some aspects, substitution patterns can be described according PATENT ATTORNEY DOCKET NO.50858-153WO4 to the scheme AnY, wherein A is the single letter code corresponding to the amino acid naturally or originally present at position n, and Y is the substituting amino acid residue. In some aspects, substitution patterns can be described according to the scheme An(YZ), wherein A is the single letter code corresponding to the amino acid residue substituting the amino acid naturally or originally present at position n, and Y and Z are alternative substituting amino acid residue. In the context of the present disclosure, substitutions (even when they referred to as amino acid substitution) may be conducted at the nucleic acid level, i.e., substituting an amino acid residue with an alternative amino acid residue may be conducted by substituting the codon encoding the first amino acid with a codon encoding the second amino acid. As used herein, the terms “percent (%) sequence identity,” “percent (%) identity,” and the like, with respect to a reference nucleic acid or polypeptide sequence, is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference nucleic acid or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid or amino acid sequence identity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, percent sequence identity values may be generated using the sequence comparison computer program BLAST. As an illustration, the percent sequence identity of a given nucleic acid or amino acid sequence, A, to, with, or against a given nucleic acid or amino acid sequence, B, (which can alternatively be phrased as a given nucleic acid or amino acid sequence, A that has a certain percent sequence identity to, with, or against a given nucleic acid or amino acid sequence, B) is calculated as follows: 100 multiplied by (the fraction X / Y) where X is the number of nucleotides or amino acids scored as identical matches by a sequence alignment program (e.g., BLAST) in that program’s alignment of A and B, and where Y is the total number of nucleic acids in B. It will be appreciated that where the length of nucleic acid or amino acid sequence A is not equal to the length of nucleic acid or amino acid sequence B, the percent sequence identity of A to B will not equal the percent sequence identity of B to A. As used herein, the terms “conservative mutation,” “conservative substitution,” “conservative amino acid substitution,” and the like refer to a substitution of one or more amino acids for one or more different amino acids that exhibit similar physicochemical properties, such as polarity, electrostatic charge, and / or steric volume. These properties are summarized for each of the twenty naturally-occurring amino acids in Table 1 below. PATENT ATTORNEY DOCKET NO.50858-153WO4 Table 1. Representative physicochemical properties of naturally-occurring amino acids From this table it is appreciated that the conservative amino acid families include, e.g., (i) G, A, V, L, I, P, and M; (ii) D and E; (iii) C, S and T; (iv) H, K and R; (v) N and Q; and (vi) F, Y and W. A conservative mutation or substitution is therefore one that substitutes one amino acid for a member of the same amino acid family (e.g., a substitution of Ser for Thr or Lys for Arg). As used herein, the term “conjugate” refers to a compound formed by the chemical bonding of a reactive functional group of one molecule with an appropriately reactive functional group of another molecule. Conjugates may additionally be produced, e.g., as two polypeptide domains covalently bound to one another as part of a single polypeptide chain that is synthesized by the translation of a single RNA transcript encoding both polypeptides in frame with one another. PATENT ATTORNEY DOCKET NO.50858-153WO4 As used herein, the term “sequence optimization” refers to a process or series of processes by which nucleobases in a reference nucleic acid sequence are replaced with alternative nucleobases, resulting in a nucleic acid sequence with improved properties, e.g., improved protein expression or decreased immunogenicity. In general, the goal in sequence optimization is to produce a synonymous nucleotide sequence than encodes the same polypeptide sequence encoded by the reference nucleotide sequence. Thus, there are no amino acid substitutions (as a result of codon optimization) in the polypeptide encoded by the codon optimized nucleotide sequence with respect to the polypeptide encoded by the reference nucleotide sequence. As used herein, the terms “codon substitution” or “codon replacement” in the context of sequence optimization refer to replacing a codon present in a reference nucleic acid sequence with another codon. A codon can be substituted in a reference nucleic acid sequence, for example, via chemical peptide synthesis or through recombinant methods known in the art. Accordingly, references to a “substitution" or "replacement" at a certain location in a nucleic acid sequence (e.g., an mRNA) or within a certain region or subsequence of a nucleic acid sequence (e.g., an mRNA) refer to the substitution of a codon at such location or region with an alternative codon. As used herein, the terms "coding region" and "region encoding" and grammatical variants thereof, refer to an Open Reading Frame (ORF) in a polynucleotide that upon expression yields a polypeptide or protein. Term “open reading frame,” in turn, refers to a segment or region of a nucleic acid molecule (e.g., mRNA molecule) that encodes a polypeptide. The ORF comprises a continuous stretch of non-overlapping, in-frame codons, beginning with the initiation codon and ending with a stop codon, and is translated by the ribosome. As used herein, the term “contacting” means establishing a physical connection between two or more entities. For example, contacting a mammalian cell with a nanoparticle composition means that the mammalian cell and a nanoparticle are made to share a physical connection. Methods of contacting cells with external entities both in vivo and ex vivo are well known in the biological arts. For example, contacting a nanoparticle composition and a mammalian cell disposed within a mammal can be performed by varied routes of administration (e.g., intravenous, intramuscular, intradermal, and subcutaneous) and can involve varied amounts of nanoparticle compositions. Moreover, more than one mammalian cell can be contacted by a nanoparticle composition. As used herein, the term “delivering” means providing an entity to a destination. For example, delivering a polynucleotide to a subject can involve administering a nanoparticle composition including the polynucleotide to the subject (e.g., by an intravenous, intramuscular, intradermal, or subcutaneous route). Administration of a nanoparticle composition to a mammal or mammalian cell can involve contacting one or more cells with the nanoparticle composition. As used herein, "delivery agent" refers to any substance that facilitates, at least in part, the in vivo, in vitro, or ex vivo delivery of a polynucleotide to targeted cells. As used herein, "expression" of a nucleic acid sequence refers to one or more of the following events: (1) production of an mRNA template from a DNA sequence (e.g., by transcription); (2) processing of an mRNA transcript (e.g., by splicing, editing, 5′ cap formation, and / or 3′ end processing); (3) PATENT ATTORNEY DOCKET NO.50858-153WO4 translation of an mRNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein. As used herein, the term “lipid nanoparticle” refers to a transfer vehicle including one or more lipids (e.g., cationic lipids, non-cationic lipids, and PEG-modified lipids). Exemplary lipid nanoparticles are formulated to deliver one or more mRNA to one or more target cells. Examples of suitable lipids include, for example, the phosphatidyl compounds (e.g., phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerebrosides, and gangliosides). Lipid nanoparticles may contain a cationic lipid, or a lipid species with a net positive charge at a selected pH (e.g., physiological pH), to encapsulate and / or enhance the delivery of mRNA into the target cells. As used herein, the term “helper lipid” refers to a compound or molecule that includes a lipidic moiety (for insertion into a lipid layer, e.g., lipid bilayer) and a polar moiety (for interaction with physiologic solution at the surface of the lipid layer). Typically, the helper lipid is a phospholipid. A function of the helper lipid is to “complement” the amino lipid and increase the fusogenicity of the bilayer and / or to help facilitate endosomal escape, e.g., of nucleic acid delivered to cells. Helper lipids are also believed to be a key structural component to the surface of the LNP. As used herein, the term “ionizable amino lipid” includes those lipids having one, two, three, or more fatty acid or fatty alkyl chains and a pH-titratable amino head group (e.g., an alkylamino or dialkylamino head group). An ionizable amino lipid is typically protonated (i.e., positively charged) at a pH below the pKa of the amino head group and is substantially not charged at a pH above the pKa. Such ionizable amino lipids include, but are not limited to dLin-MC3-DMA (MC3), (13Z,165Z)-N,N-dimethyl-3- nonydocosa-13-16-dien-1-amine (L608), among others. As used herein, a "linker" refers to a group of atoms, e.g., 10-1,000 atoms, and can be comprised of the atoms or groups such as, but not limited to, carbon, amino, alkylamino, oxygen, sulfur, sulfoxide, sulfonyl, carbonyl, and imine. The linker can be attached to a modified nucleoside or nucleotide on the nucleobase or sugar moiety at a first end, and to a payload, e.g., a detectable or therapeutic agent, at a second end. The linker can be of sufficient length as to not interfere with incorporation into a nucleic acid sequence. The linker can be used for any useful purpose, such as to form polynucleotide multimers (e.g., through linkage of two or more chimeric polynucleotides molecules or IVT polynucleotides) or polynucleotides conjugates, as well as to administer a payload, as described herein. Examples of chemical groups that can be incorporated into the linker include, but are not limited to, alkyl, alkenyl, alkynyl, amido, amino, ether, thioether, ester, alkylene, heteroalkylene, aryl, or heterocyclyl, each of which can be optionally substituted, as described herein. Examples of linkers include, but are not limited to, unsaturated alkanes, polyethylene glycols (e.g., ethylene or propylene glycol monomeric units, e.g., diethylene glycol, dipropylene glycol, triethylene glycol, tripropylene glycol, tetraethylene glycol, or tetraethylene glycol), and dextran polymers and derivatives thereof., Other examples include, but are not limited to, cleavable moieties within the linker, such as, for example, a disulfide bond (-S-S-) or an azo bond (-N=N-), which can be cleaved using a reducing agent or photolysis. Non-limiting examples of a selectively cleavable bond include an amido bond can be cleaved for example by the use of tris(2- carboxyethyl)phosphine (TCEP), or other reducing agents, and / or photolysis, as well as an ester bond can be cleaved for example by acidic or basic hydrolysis. PATENT ATTORNEY DOCKET NO.50858-153WO4 As used herein, the terms “messenger RNA” or “mRNA” refer to any polynucleotide which encodes a polypeptide of interest and which is capable of being translated to produce the encoded polypeptide of interest in vitro, in vivo, in situ, or ex vivo. Traditionally, the basic components of an mRNA molecule include a coding region, a 5’UTR, a 3’UTR, a 5’ cap, and a poly-A tail. As used herein the term "modified" refers to a changed state or structure of a molecule of the present disclosure. Molecules can be modified in many ways, including chemically, structurally, and functionally. In some embodiments, the mRNA molecules of the present disclosure are modified by the introduction of non-natural nucleosides and / or nucleotides, e.g., as it relates to the natural ribonucleotides A, T, U, G, and / or C. A “modified nucleoside,” as that term is used herein, refers to a nucleoside having a modification at either the ribose or the nucleobase moiety within the nucleoside structure relative to unmodified A / T / U / G / C nucleosides. Accordingly, examples of “modified nucleosides” include “2’-modified nucleosides,” which contain a modification at the 2’ position of the ribose within the core nucleoside structure, as well as ”nucleobase- modified nucleosides,” which contain modifications at the nucleobase moiety.2’-modified nucleosides described herein may be referred to in the form “2’ (substituent) nucleoside,” such as 2’-methoxy nucleoside, 2’-fluoro nucleoside, 2’-NH2 nucleoside, and the like. In each instance, the term refers to a nucleoside containing the indicated substituent at the 2’ position of the nucleoside’s ribose ring. Similarly, “modified internucleoside linkages” refer to linkages between nucleosides, wherein the linkages have a modification relative to a standard phosphodiester substituent that occurs naturally. “Unmodified” nucleosides and internucleoside linkages, in contrast, are the canonical A, U / T, G, and C nucleosides, as well as the phosphodiester internucleoside linkage, all of which occur naturally. Examples of unmodified nucleosides, in an RNA context, are the A, U, G, and C ribonucleosides, devoid of synthetic chemical substituents. Examples of unmodified nucleosides, in a DNA context, are the A, T, G, and C 2’- deoxynucleosides, devoid of synthetic chemical substituents. Similarly, examples of unmodified internucleoside linkages are phosphodiester linkages. As used herein, the terms “modified messenger RNA” or “modified mRNA” refer to mRNA polynucleotides that include naturally occurring and / or non-naturally occurring modifications, for example, of a sugar, a nucleobase, or an internucleoside linkage (e.g., to a linking phosphate, to a phosphodiester linkage, or to the phosphodiester backbone). Non-natural modified nucleotides may be introduced during synthesis of post-synthesis of the polynucleotides to achieve desired functions or properties. The modifications may be present on an internucleoside linkage, purine or pyrimidine base, or sugar. The modification may be introduced with chemical synthesis or with a polymerase enzyme at the terminal of a chain or anywhere else in the chain. Any of the regions of a polynucleotide may be chemically modified. As used herein, the term “initiation codon”, used interchangeably with the term “start codon”, refers to the first codon of an open reading frame that is translated by the ribosome and is comprised of a triplet of linked adenine-uracil-guanine nucleobases. The initiation codon is depicted by the first letter codes of adenine (A), uracil (U), and guanine (G) and is often written simply as “AUG”. Although natural mRNAs may use codons other than AUG as the initiation codon, which are referred to herein as “alternative initiation codons”, the initiation codons of polynucleotides described herein use the AUG codon. During the process of translation initiation, the sequence comprising the initiation codon is PATENT ATTORNEY DOCKET NO.50858-153WO4 recognized via complementary base-pairing to the anticodon of an initiator tRNA (Met-tRNAiMet) bound by the ribosome. Open reading frames may contain more than one AUG initiation codon, which are referred to herein as “alternate initiation codons”. The initiation codon plays an important role in translation initiation. The initiation codon is the first codon of an open reading frame that is translated by the ribosome. Typically, the initiation codon comprises the nucleotide triplet AUG, however, in some instances translation initiation can occur at other codons comprised of distinct nucleotides. The initiation of translation in eukaryotes is a multistep biochemical process that involves numerous protein-protein, protein-RNA, and RNA-RNA interactions between messenger RNA molecules (mRNAs), the 40S ribosomal subunit, other components of the translation machinery (e.g., eukaryotic initiation factors; eIFs). The current model of mRNA translation initiation postulates that the pre-initiation complex (alternatively “43S pre-initiation complex”; abbreviated as “PIC”) translocates from the site of recruitment on the mRNA (typically the 5′ cap) to the initiation codon by scanning nucleotides in a 5′ to 3′ direction until the first AUG codon that resides within a specific translation-promotive nucleotide context (the Kozak sequence) is encountered (Kozak (1989) J Cell Biol 108:229-241). Scanning by the PIC ends upon complementary base-pairing between nucleotides comprising the anticodon of the initiator Met-tRNAiMettransfer RNA and nucleotides comprising the initiation codon of the mRNA. Productive base-pairing between the AUG codon and the Met-tRNAiMetanticodon elicits a series of structural and biochemical events that culminate in the joining of the large 60S ribosomal subunit to the PIC to form an active ribosome that is competent for translation elongation. The term “Kozak sequence” (also referred to as “Kozak consensus sequence”) refers to a translation initiation enhancer element to enhance expression of a gene or open reading frame, and which in eukaryotes, is located in the 5′ UTR. The Kozak consensus sequence was originally defined as the sequence GCCRCC (SEQ ID NO: 1, where R = a purine, following an analysis of the effects of single mutations surrounding the initiation codon (AUG) on translation of the preproinsulin gene (Kozak (1986) Cell 44:283-292). Polynucleotides disclosed herein comprise a Kozak consensus sequence, or a derivative or modification thereof. (Examples of translational enhancer compositions and methods of use thereof, see U.S. Pat. No.5,807,707 to Andrews et al., incorporated herein by reference in its entirety; U.S. Pat. No.5,723,332 to Chernajovsky, incorporated herein by reference in its entirety; U.S. Pat. No. 5,891,665 to Wilson, incorporated herein by reference in its entirety.) As used herein, the term “nucleobase” (alternatively “nucleotide base” or “nitrogenous base”) refers to a purine or pyrimidine heterocyclic compound found in nucleic acids, including any derivatives or analogs of the naturally occurring purines and pyrimidines that confer improved properties (e.g., binding affinity, nuclease resistance, chemical stability) to a nucleic acid or a portion or segment thereof. Adenine, cytosine, guanine, thymine, and uracil are the nucleobases predominately found in natural nucleic acids. Other natural, non-natural, and / or synthetic nucleobases, as known in the art and / or described herein, can be incorporated into nucleic acids. Unless otherwise specified, the nucleobase sequence of a SEQ ID NO described herein encompasses both natural nucleobases and chemically modified nucleobases (e.g., a “U” designation in a SEQ ID NO encompasses both uracil and chemically modified uracil). As used herein, the term “nucleoside” refers to a compound containing a sugar molecule (e.g., a ribose in RNA or a deoxyribose in DNA), or derivative or analog thereof, covalently linked to a nucleobase (e.g., a purine or pyrimidine), or a derivative or analog thereof (also referred to herein as “nucleobase”), PATENT ATTORNEY DOCKET NO.50858-153WO4 but lacking an internucleoside linking group (e.g., a phosphate group). As used herein, the term “nucleotide” refers to a nucleoside covalently bonded to an internucleoside linking group (e.g., a phosphate group), or any derivative, analog, or modification thereof that confers improved chemical and / or functional properties (e.g., binding affinity, nuclease resistance, chemical stability) to a nucleic acid or a portion or segment thereof. As used herein, the terms "nucleic acid" and “polynucleotide” are used interchangeably. In their broadest sense, these terms include any compound and / or substance that comprises a polymer of nucleotides. Exemplary nucleic acids or polynucleotides of the present disclosure include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a β- D-ribo configuration, α-LNA having an α-L-ribo configuration (a diastereomer of LNA), 2′-amino-LNA having a 2′-amino functionalization, and 2′-amino- α-LNA having a 2′-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) or hybrids or combinations thereof. Nucleic acid molecules of the disclosure may be, for example, triple-, double-, or single-stranded deoxyribonucleic acid ("DNA"), as well as triple-, double- and single-stranded ribonucleic acid ("RNA"). This term also includes modified, for example, by alkylation, and / or by capping, and unmodified forms of the corresponding unmodified nucleic acid. In particular aspects, the nucleic acid comprises an mRNA. In other aspect, the mRNA is a synthetic mRNA. In some aspects, the synthetic mRNA comprises at least one unnatural nucleobase. In some aspects, all nucleobases of a certain class have been replaced with unnatural nucleobases (e.g., all uridines in a polynucleotide disclosed herein can be replaced with an unnatural nucleobase, e.g., 1-methylpseudouridine). In some aspects, the polynucleotide (e.g., a synthetic RNA or a synthetic DNA) comprises only natural nucleobases, i.e., A (adenosine), G (guanosine), C (cytidine), and T (thymidine) in the case of a synthetic DNA, or A, C, G, and U (uridine) in the case of a synthetic RNA. The skilled artisan will appreciate that the T bases in the codon maps disclosed herein are present in DNA, whereas the T bases would be replaced by U bases in corresponding RNAs. For example, a codon-nucleotide sequence disclosed herein in DNA form, e.g., a vector or an in-vitro translation (IVT) template, would have its T bases transcribed as U based in its corresponding transcribed mRNA. In this respect, both codon-optimized DNA sequences (comprising T) and their corresponding mRNA sequences (comprising U) are considered codon-optimized nucleotide sequence of the present disclosure. A skilled artisan would also understand that equivalent codon-maps can be generated by replacing one or more bases with non-natural bases. Thus, e.g., a TTC codon (DNA map) would correspond to a UUC codon (RNA map), which in turn would correspond to a ΨΨC codon (RNA map in which U has been replaced with pseudouridine). Standard A-T and G-C base pairs form under conditions which allow the formation of hydrogen bonds between the N3-H and C4-oxy of thymidine and the N1 and C6-NH2, respectively, of adenosine and between the C2-oxy, N3 and C4-NH2, of cytidine and the C2-NH2, N′—H and C6-oxy, respectively, of guanosine. Thus, for example, guanosine (2-amino-6-oxy-9-β-D-ribofuranosyl-purine) can be modified to form isoguanosine (2-oxy-6-amino-9-β-D-ribofuranosyl-purine). Such modification results in a nucleoside base which will no longer effectively form a standard base pair with cytosine. However, modification of cytosine (1-β-D-ribofuranosyl-2-oxy-4-amino-pyrimidine) to form isocytosine (1-β-D- PATENT ATTORNEY DOCKET NO.50858-153WO4 ribofuranosyl-2-amino-4-oxy-pyrimidine-) results in a modified nucleotide which will not effectively base pair with guanosine but will form a base pair with isoguanosine (U.S. Pat. No.5,681,702 to Collins et al.). Isocytosine is available from Sigma Chemical Co. (St. Louis, Mo.); isocytidine can be prepared by the method described by Switzer et al. (1993) Biochemistry 32:10489-10496 and references cited therein; 2′- deoxy-5-methyl-isocytidine can be prepared by the method of Tor et al., 1993, J. Am. Chem. Soc. 115:4461-4467 and references cited therein; and isoguanine nucleotides can be prepared using the method described by Switzer et al., 1993, supra, and Mantsch et al., 1993, Biochem.14:5593-5601, or by the method described in U.S. Pat. No.5,780,610 to Collins et al. Other nonnatural base pairs can be synthesized by the method described in Piccirilli et al., 1990, Nature 343:33-37, for the synthesis of 2,6- diaminopyrimidine and its complement (1-methylpyrazolo-[4,3]pyrimidine-5,7-(4H,6H)-dione. Other such modified nucleotide units which form unique base pairs are known, such as those described in Leach et al. (1992) J. Am. Chem. Soc.114:3675-3683 and Switzer et al., supra. Nucleotides are referred to by their commonly accepted single-letter codes. Unless otherwise indicated, nucleic acids are written left to right in 5′ to 3′ orientation. Nucleobases are referred to herein by their commonly known one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Accordingly, A represents adenine, C represents cytosine, G represents guanine, T represents thymine, U represents uracil. The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer can comprise modified amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids such as homocysteine, ornithine, p-acetylphenylalanine, D-amino acids, and creatine), as well as other modifications known in the art. The preceding terms, as used herein, refer to proteins, polypeptides, and peptides of any size, structure, or function. Polypeptides include encoded polynucleotide products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing. A polypeptide can be a monomer or can be a multi-molecular complex such as a dimer, trimer or tetramer. They can also comprise single chain or multichain polypeptides. Most commonly disulfide linkages are found in multichain polypeptides. The term polypeptide can also apply to amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid. In some embodiments, a "peptide" can be less than or equal to 50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long. Amino acids are referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. As used herein, the term “operatively linked” in the context of a polynucleotide fragment is intended to mean that the two polynucleotide fragments are joined such that the amino acid sequences encoded by the two polynucleotide fragments remain in-frame. PATENT ATTORNEY DOCKET NO.50858-153WO4 As used herein, the term "pharmacokinetic" refers to any one or more properties of a molecule or compound as it relates to the determination of the fate of substances administered to a living organism. Pharmacokinetics is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as ADME where: (A) Absorption is the process of a substance entering the blood circulation; (D) Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body; (M) Metabolism (or Biotransformation) is the irreversible transformation of parent compounds into daughter metabolites; and (E) Excretion (or Elimination) refers to the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue. As used herein, the terms “subject” and “patient” refer to an organism that receives treatment for a particular disease or condition. Examples of subjects and patients include mammals, such as humans, primates, pigs, goats, rabbits, hamsters, cats, dogs, guinea pigs, members of the bovidae family (such as cattle, bison, buffalo, and yaks, among others), sheep, and horses, among others. A patient that may be treated using the compositions and methods described herein may have an established disease, in which case the patient has been diagnosed as having the disease and has shown symptoms of the disease for a prolonged period of time (e.g., over the course of days, weeks, months, or years). Alternatively, a patient may be symptomatic for a particular disease, but has yet to be diagnosed with the disease by a physician. Other patients that may be treated using the compositions and methods described herein include those that have been diagnosed as having a particular disease and may or may not be showing symptoms of the disease as of yet. For example, a patient eligible for treatment with the compositions and methods described herein may be described as diagnosed but asymptomatic if the patient has received a diagnosis of a disease, even though the patient may not yet be showing symptoms thereof. As used herein, "transfection" refers to the introduction of a polynucleotide (e.g., exogenous nucleic acids) into a cell wherein a polypeptide encoded by the polynucleotide is expressed (e.g., mRNA) or the polypeptide modulates a cellular function (e.g., siRNA, miRNA). As used herein, "expression" of a nucleic acid sequence refers to translation of a polynucleotide (e.g., an mRNA) into a polypeptide or protein and / or post-translational modification of a polypeptide or protein. Methods of transfection include, but are not limited to, chemical methods, physical treatments and cationic lipids or mixtures. As used herein, the terms “treat” or “treatment” refer to therapeutic treatment, in which the object is to inhibit or slow down (lessen) an undesired physiological change or disorder. Beneficial or desired clinical results of treatment include, without limitation, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Those in need of treatment include those already having the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be inhibited. As used herein, the term "effective amount" of an agent is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an "effective amount" depends upon the context in which it is being applied. For example, in the context of administering an agent that treats a protein deficiency, an effective amount of an agent is, for example, an amount of mRNA expressing sufficient the desired protein to ameliorate, reduce, eliminate, or prevent the symptoms PATENT ATTORNEY DOCKET NO.50858-153WO4 associated with the corresponding protein deficiency, as compared to the severity of the symptom observed without administration of the agent. The term "effective amount" can be used interchangeably with "effective dose," "therapeutically effective amount," or "therapeutically effective dose." As used herein in the context of treating a subject undergoing a skincare regimen, the term “aging” refers to the gradual process by which, over time, a subject’s skin naturally undergoes one or more changes that result in a reduction the quantity of collagen (e.g., alpha-1 type I collagen, COL1A1) in the subject’s skin. Aging may accompany a skin degeneration (e.g., loss of physiological function and / or reduction of structural integrity, among other phenotypes described herein. Environmental factors that can accelerate skin aging include ultraviolet (UV) ray exposure, among other factors. As used herein, the term “skin firmness” refers to the ability of the skin to resist physical extension. Non-limiting examples of methods used to measure skin firmness include by way of extensometer devices that are publicly available. As used herein, the term “skin elasticity” refers to the ability of the skin to return to its original visual appearance following physical expansion or compression. Non-limiting examples of methods used to measure skin firmness include by way of cutometer devices that are publicly available. As used herein, the terms “skin wrinkling,” “wrinkles,” and the like refer to a physical manifestation of a decrease in skin integrity in which the skin may sag or exhibit laxity or looseness. Wrinkles generally appear as fine or coarse lines in a subject’s skin. Examples of wrinkles include, without limitation, eye wrinkles, sagitta, lacrimal canals, nasal wrinkles, forehead wrinkles, glabellar lines, nasolabial folds, vertical lip lines, perioral marionette lines, and mental creases, among others. As used herein, the term “dermal atrophy” refers to a decrease in the thickness of a subject’s skin. As used herein, the terms “alpha-1 type I collagen” (and its abbreviation, COL1A1) refer to a wild- type human alpha-1 type I collagen protein (for example, a collagen protein having the amino acid sequence of NCBI Reference Sequence: NP_000079.2), as well as functional variants thereof (e.g., variants that differ from a wild-type COL1A1 polypeptide by way of one or more amino acid substitutions, insertions, and / or deletions). Exemplary COL1A1 polypeptides of the disclosure include variants of NCBI Reference Sequence: NP_000079.2 that have, e.g., at least 70% sequence identity thereto and that retain a biological function of wild-type COL1A1 (for example, variants having at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to NCBI Reference Sequence: NP_000079.2). A “functional fragment” of COL1A1, as the term is used herein, refers to a smaller portion of a full- length COL1A1 polypeptide that retains the ability to assemble with one or more other COL1A1 fragments so as to form an active COL1A1 polypeptide (i.e., a COL1A1 polypeptide having a biological function of wild-type COL1A1). COL1A1 functional fragments useful in the context of the disclosure include those having one or more amino acid substitutions, insertions, or deletions relative to a fragment of equal length within a wild-type COL1A1 protein sequence, such as NCBI Reference Sequence: NP_000079.2. Exemplary COL1A1 functional fragments useful in the present disclosure include polypeptides having an PATENT ATTORNEY DOCKET NO.50858-153WO4 amino acid sequence that is at least 70% identical (e.g., at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to a fragment of equal length within a wild-type COL1A1 protein sequence, such as NCBI Reference Sequence: NP_000079.2. As used herein, “methods of administration” can include intravenous, intramuscular, intradermal, subcutaneous, or other methods of delivering a composition to a subject. A method of administration can be selected to target delivery (e.g., to specifically deliver) to a specific region or system of a body. As used herein, the terms “internal linker,” “internal spacer” and the like refer to a linking group between nucleosides that is not a traditional internucleoside linkage. Internal linkers may be, for example, a linear or branched alkyl chain or a linear or branched heteroalkyl chain (e.g., a polyethylene glycol chain). In some embodiments, any internal linker described herein may contain from 1 to 50 atoms, from 1 to 40 atoms, from 3 to 30 atoms, from 3 to 25 atoms, from 5 to 30 atoms, from 5 to 25 atoms, from 3 to 15 atoms, 1 atom, 2 atoms, 3 atoms, 4 atoms, 5 atoms, 6 atoms, 7 atoms, 8 atoms, 9 atoms, 10 atoms, 11 atoms, 12 atoms, 13 atoms, 14 atoms, 15 atoms, 16 atoms, 17 atoms, 18 atoms, 19 atoms, 20 atoms, 21 atoms, 22 atoms, 23 atoms, 24 atoms, 25 atoms, 26 atoms, 27 atoms, 28 atoms, 29 atoms, 30 atoms, 31 atoms, 32 atoms, 33 atoms, 34 atoms, 35 atoms, 36 atoms, 37 atoms, 38 atoms, 39 atoms, 40 atoms, 41 atoms, 42 atoms, 43 atoms, 44 atoms, 45 atoms, 46 atoms, 47 atoms, 48 atoms, 49 atoms, or 50 atoms. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable excipient," as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients can include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspension or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the PATENT ATTORNEY DOCKET NO.50858-153WO4 disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p.1418, Pharmaceutical Salts: Properties, Selection, and Use, P.H. Stahl and C.G. Wermuth (eds.), Wiley-VCH, 2008, and Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977), each of which is incorporated herein by reference in its entirety. The term "pharmaceutically acceptable solvate," as used herein, means a compound of the present disclosure wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. For example, solvates can be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6- tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a "hydrate." As used herein, the term "alkyl", "alkyl group", or "alkylene" means a linear or branched, saturated hydrocarbon including one or more carbon atoms (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms), which is optionally substituted. The notation "C1-14 alkyl" means an optionally PATENT ATTORNEY DOCKET NO.50858-153WO4 substituted linear or branched, saturated hydrocarbon including 1-14 carbon atoms. Unless otherwise specified, an alkyl group described herein refers to both unsubstituted and substituted alkyl groups. As used herein, the term "alkenyl", "alkenyl group", or "alkenylene" means a linear or branched hydrocarbon including two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one double bond, which is optionally substituted. The notation "C2-14 alkenyl" means an optionally substituted linear or branched hydrocarbon including 2-14 carbon atoms and at least one carbon-carbon double bond. An alkenyl group may include one, two, three, four, or more carbon-carbon double bonds. For example, C18 alkenyl may include one or more double bonds. A C18 alkenyl group including two double bonds may be a linoleyl group. Unless otherwise specified, an alkenyl group described herein refers to both unsubstituted and substituted alkenyl groups. As used herein, the term "alkynyl", "alkynyl group", or "alkynylene" means a linear or branched hydrocarbon including two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one carbon-carbon triple bond, which is optionally substituted. The notation "C2-14 alkynyl" means an optionally substituted linear or branched hydrocarbon including 2-14 carbon atoms and at least one carbon-carbon triple bond. An alkynyl group may include one, two, three, four, or more carbon-carbon triple bonds. For example, C18 alkynyl may include one or more carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group described herein refers to both unsubstituted and substituted alkynyl groups. As used herein, the term "carbocycle" or "carbocyclic group" means an optionally substituted mono- or multi-cyclic system including one or more rings of carbon atoms. Rings may be three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty membered rings. The notation "C3-6 carbocycle" means a carbocycle including a single ring having 3-6 carbon atoms. Carbocycles may include one or more carbon-carbon double or triple bonds and may be non-aromatic or aromatic (e.g., cycloalkyl or aryl groups). Examples of carbocycles include cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and 1,2 dihydronaphthyl groups. The term "cycloalkyl" as used herein means a non-aromatic carbocycle and may or may not include any double or triple bond. Unless otherwise specified, carbocycles described herein refer to both unsubstituted and substituted carbocycle groups, i.e., optionally substituted carbocycles. As used herein, the term "heterocycle" or "heterocyclic group" means an optionally substituted mono- or multi-cyclic system including one or more rings, where at least one ring includes at least one heteroatom. Heteroatoms may be, for example, nitrogen, oxygen, or sulfur atoms. Rings may be three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen membered rings. Heterocycles may include one or more double or triple bonds and may be non-aromatic or aromatic (e.g., heterocycloalkyl or heteroaryl groups). Examples of heterocycles include imidazolyl, imidazolidinyl, oxazolyl, oxazolidinyl, thiazolyl, thiazolidinyl, pyrazolidinyl, pyrazolyl, isoxazolidinyl, isoxazolyl, isothiazolidinyl, isothiazolyl, morpholinyl, pyrrolyl, pyrrolidinyl, furyl, tetrahydrofuryl, thiophenyl, pyridinyl, piperidinyl, quinolyl, and isoquinolyl groups. The term "heterocycloalkyl" as used herein means a non- aromatic heterocycle and may or may not include any double or triple bond. Unless otherwise specified, PATENT ATTORNEY DOCKET NO.50858-153WO4 heterocycles described herein refer to both unsubstituted and substituted heterocycle groups, i.e., optionally substituted heterocycles. As used herein, the term "heteroalkyl", "heteroalkenyl", or "heteroalkynyl", refers respectively to an alkyl, alkenyl, alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. Unless otherwise specified, heteroalkyls, heteroalkenyls, or heteroalkynyls described herein refers to both unsubstituted and substituted heteroalkyls, heteroalkenyls, or heteroalkynyls, i.e., optionally substituted heteroalkyls, heteroalkenyls, or heteroalkynyls. As used herein, a "biodegradable group" is a group that may facilitate faster metabolism of a lipid in a mammalian entity. A biodegradable group may be selected from the group consisting of, but is not limited to, -C(O)O-, -OC(O)-, -C(O)N(R')-, -N(R')C(O)-, -C(O)-, -C(S)-, -C(S)S-, -SC(S)-, -CH(OH)-, - P(O)(OR')O-, -S(O)2-, an aryl group, and a heteroaryl group. As used herein, an "aryl group" is an optionally substituted carbocyclic group including one or more aromatic rings. Examples of aryl groups include phenyl and naphthyl groups. As used herein, a "heteroaryl group" is an optionally substituted heterocyclic group including one or more aromatic rings. Examples of heteroaryl groups include pyrrolyl, furyl, thiophenyl, imidazolyl, oxazolyl, and thiazolyl. Both aryl and heteroaryl groups may be optionally substituted. For example, M and M' can be selected from the non-limiting group consisting of optionally substituted phenyl, oxazole, and thiazole. In the Formulas herein, M and M' can be independently selected from the list of biodegradable groups above. Unless otherwise specified, aryl or heteroaryl groups described herein refer to both unsubstituted and substituted groups, i.e., optionally substituted aryl or heteroaryl groups. Alkyl, alkenyl, and cyclyl (e.g., carbocyclyl and heterocyclyl) groups may be optionally substituted unless otherwise specified. Optional substituents may be selected from the group consisting of, but are not limited to, a halogen atom (e.g., a chloride, bromide, fluoride, or iodide group), a carboxylic acid (e.g., C(O)OH), an alcohol (e.g., a hydroxyl, OH), an ester (e.g., C(O)OR OC(O)R), an aldehyde (e.g., C(O)H), a carbonyl (e.g., C(O)R, alternatively represented by C=O), an acyl halide (e.g., C(O)X, in which X is a halide selected from bromide, fluoride, chloride, and iodide), a carbonate (e.g., OC(O)OR), an alkoxy (e.g., OR), an acetal (e.g., C(OR)2R"", in which each OR are alkoxy groups that can be the same or different and R"" is an alkyl or alkenyl group), a phosphate (e.g., P(O)43-), a thiol (e.g., SH), a sulfoxide (e.g., S(O)R), a sulfinic acid (e.g., S(O)OH), a sulfonic acid (e.g., S(O)2OH), a thial (e.g., C(S)H), a sulfate (e.g., S(O)42-), a sulfonyl (e.g., S(O)2 ), an amide (e.g., C(O)NR2, or N(R)C(O)R), an azido (e.g., N3), a nitro (e.g., NO2), a cyano (e.g., CN), an isocyano (e.g., NC), an acyloxy (e.g., OC(O)R), an amino (e.g., NR2, NRH, or NH2), a carbamoyl (e.g., OC(O)NR2, OC(O)NRH, or OC(O)NH2), a sulfonamide (e.g., S(O)2NR2, S(O)2NRH, S(O)2NH2, N(R)S(O)2R, N(H)S(O)2R, N(R)S(O)2H, or N(H)S(O)2H), an alkyl group, an alkenyl group, and a cyclyl (e.g., carbocyclyl or heterocyclyl) group. In any of the preceding, R is an alkyl or alkenyl group, as defined herein. In some embodiments, the substituent groups themselves may be further substituted with, for example, one, two, three, four, five, or six substituents as defined herein. For example, a C1-6 alkyl group may be further substituted with one, two, three, four, five, or six substituents as described herein. PATENT ATTORNEY DOCKET NO.50858-153WO4 Compounds of the disclosure that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and / or hydrogen peroxides) to afford other compounds of the disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N- oxide derivative (which can be designated as N→O or N+-O-). Furthermore, in other instances, the nitrogens in the compounds of the disclosure can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives. BRIEF DESCRIPTION OF THE DRAWINGS FIGS.1A and 1B are graphs that show the results of an experiment in which modified, synthetic RNA molecules (“synRNA molecules”) were tested for their ability to successfully express a reporter protein in cells. As is described in Example 1, below, in this experiment, cells were transfected with a synthetic RNA molecule encoding a C-terminal fragment (CTF) of green fluorescent protein (GFP). Independent of this transfection, the cells stably expressed a polypeptide containing the remainder of the GFP protein. Expression of the CTF acts as a reporter in this assay because, if a functional CTF is successfully expressed, the CTF noncovalently assembles with the stably expressed GFP remainder, thereby reconstituting the active GFP protein, which manifests as green fluorescence. Similarly, if the CTF is either not expressed or is nonfunctional, then active GFP is not reconstituted and, consequently, no green fluorescence is observed. In this way, green fluorescence in this assay acts as a readout for expression of a functional CTF peptide. In Example 1, cells were monitored for a period of 72 hours post-transfection of the synRNA, with the results for each RNA molecule shown in FIG.1A (GFP intensity) and FIG.1B (cell confluence). FIGS.2A and 2B are graphs that show the results of an experiment in which modified, synthetic RNA molecules were tested for their ability to successfully express protein in cells. As is explained above, in this experiment, cells were transfected with a synthetic RNA encoding a CTF of GFP. The synthetic RNA molecule contained various chemical modifications. Independent of this transfection, the cells stably expressed the remainder of the GFP protein, such that expression of the functional CTF would lead to noncovalent reconstitution of an active GFP protein, allowing green fluorescence to serve as a proxy for successful CTF expression. Fluorescence was monitored for a period of 72 hours, with the results for each RNA molecule shown in FIG.2A (GFP intensity) and FIG.2B (a zoomed-in portion of FIG.2A). These graphs show that molecules containing certain types of chemical modifications exhibit increased protein expression and heightened stability. FIG.3 shows the results of an experiment validating that the fidelity of residue Glu222 of GFP is critical for GFP’s fluorescent activity. FIG.3 evaluates the effect of various amino acid substitutions at residue Glu222 of GFP on the fluorescence of the resulting protein. As FIG.3 shows, Glu222 is a critical residue for GFP’s fluorescence, as changes that remove glutamate from this position substantially reduce fluorescent activity. These results validate position Glu222 of GFP as an insertion site for the chemical PATENT ATTORNEY DOCKET NO.50858-153WO4 modifications that were investigated in the working examples, below: If the chemical modification is tolerated by the ribosome and leads to expression of glutamate at position 222, the ensuing GFP will be functional, with fluorescence acting as a proxy for successful CTF expression. If, however, the chemical modification is not tolerated by the ribosome and does not lead to expression of glutamate at position 222 and / or leads the ribosome to incorporate an incorrect amino acid, the ensuring GFP will not be fluorescently active, and this reduction in (or absence of) fluorescence will serve as a proxy for the failure to express functional CTF. FIGS.4A, 4B, 4C, and 4D are graphs that show the results of experiments in which modified, synthetic RNA molecules were tested for their ability to successfully express protein in cells. As is explained above, in this experiment, cells were transfected with a synthetic RNA encoding a CTF of GFP. The synthetic RNA molecule contained various chemical modifications. Independent of this transfection, the cells stably expressed the remainder of the GFP protein, such that expression of the functional CTF would lead to noncovalent reconstitution of an active GFP protein, allowing green fluorescence to serve as a proxy for successful CTF expression. Fluorescence was monitored for a period of 96 hours, with the results for each RNA molecule shown in FIG.4A (RNA 1, 11, and 54) FIG.4B (RNA 1, 58, and 47), FIG. 4C (RNA 1, 49, 50, 52, 51, and 53), and FIG.4D (RNA 1, 62, and 61). These graphs show that molecules containing certain types of chemical modifications, in a particular pattern, can be expressed by cells, can exhibit increased protein expression and / or heightened stability. DETAILED DESCRIPTION The present disclosure provides nucleic acid molecules (e.g., mRNA molecules), that contain synthetic chemical modifications. Such nucleic acid molecules are referred to herein as “synRNA” molecules. The synRNA molecules of the disclosure solve an important problem in the field of nucleic acid therapeutics: the need for a modification strategy that not only improves nucleic acid half-life, but that does so while preserving the ability of the nucleic acid (e.g., mRNA) to be translated by the ribosome. As is discussed in further detail in the sections that follow, there exist a wide array of chemical modifications that can be installed into a protein-coding mRNA molecule so as to impart the molecule with substituents that resist enzymatic and chemical degradation. However, many of these modifications are incompatible with a cell’s endogenous protein production machinery, effectively diminishing the utility of a significant fraction of chemical space in the context of an mRNA. The present disclosure is based on the surprising discovery that, when particular chemical substituents are installed at precise locations within a protein-encoding nucleic acid (e.g., at specific sites within the open reading frame (ORF), 5’ untranslated region (UTR), 3’ untranslated region, or poly-A tail of an mRNA), these chemical modifications serve not only to improve the stability of the resulting nucleic acid molecule, but are also unexpectedly capable of being processed by the ribosome so as to furnish protein product. In this way, the nucleic acid molecules of the disclosure represent the overlap in chemical space of synthetic modifications that augment nucleic acid stability and that are tolerated by a cell’s endogenous protein production processes. In some embodiments, the synRNA of any of the foregoing aspects or embodiments of the disclosure exhibits increased expression compared to a corresponding unmodified RNA molecule when introduced into a cell or a population of cells. In some embodiments, the maximum expression of the PATENT ATTORNEY DOCKET NO.50858-153WO4 synRNA is increased compared to the maximum expression of a corresponding unmodified RNA. In some embodiments, the total expression over a period of time (e.g., 24 hours, 48 hours, 72 hours, or 96 hours) of the synRNA is increased compared to the total expression of a corresponding unmodified RNA over the same period of time. In some embodiments, the synRNA of any of the foregoing aspects or embodiments of the disclosure exhibits increased stability compared to a corresponding unmodified RNA molecule when introduced into a cell or a population of cells. In some embodiments the synRNA exhibits increased stability over a period of time (e.g., 24 hours, 48 hours, 72 hours, 96 hours, or more) compared to a corresponding unmodified RNA. In some embodiments, the increased stability can manifest as expression that is prolonged relative to a corresponding unmodified RNA molecule (e.g., prolonged by at least 1 hour, at least 2 hours, at least 3 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or longer). The sections that follow describe exemplary synRNA molecules of the disclosure, as well as methods of using the same to express protein product in a cell, tissue, or subject of interest. 1. SynRNA molecules Exemplary nucleic acid molecules (e.g., mRNA molecules) of the disclosure are those that contain: a) at least one 5’ cap structure; b) a 5’ UTR; c) ORF encoding a polypeptide; d) a 3’ UTR; and e) a poly-A region. In some embodiments, the synRNA comprises one or more, or all, of the following features: i) a modified internucleoside linkage in the ORF; ii) a modified internucleoside linkage in the 5’ UTR; iii) a modified internucleoside linkage in the 3’ UTR; iv) a 2’ modified ribose in the 3’ UTR; v) a 2’ modified ribose in the ORF; and / or vi) a 2’ modified ribose in the poly-A region. In some embodiments, the synRNA comprises a modified internucleoside linkage in the ORF. In some embodiments, the modified internucleoside linkage in the ORF is between a third nucleoside of a first codon and a first nucleoside of a second codon. In some embodiments, the synRNA comprises a modified internucleoside linkage in the 5’ UTR. In some embodiments, the synRNA comprises a modified internucleoside linkage in the 3’ UTR. In some embodiments, the modified internucleoside linkage is selected from the group consisting of a phosphorothioate, a phosphoroselenate, a boranophosphate, a boranophosphate ester, a hydrogen phosphonate, a phosphoramidate, a phosphorodiamidate, an alkyl phosphonate, an aryl phosphonate, a phosphotriester, a phosphorodithioate, a bridged phosphoramidate, a bridged phosphorothioate, a bridged methylene-phosphonate, and an α-thio phosphate. In some embodiments, the modified internucleoside linkage is a phosphorothioate internucleoside linkage. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the synRNA comprises a 2’ modified ribose in the 3’ UTR. In some embodiments, the synRNA comprises a 2’ modified ribose in the poly-A region. In some embodiments, the 2’ modified ribose is selected from the group consisting of a 2’-deoxyribose, a 2’-OMe ribose, a 2’-O- methoxyethyl ribose (2’-MOE), a 2’-F ribose, a 2’-NH2 ribose, a 2’fluoroarabino ribose (FANA), a locked nucleic acid (LNA), and a 4’-S ribose. In some embodiments, the 2’ modified ribose is a 2’-O-methyl ribose. In some embodiments, the 2’ modified ribose is a 2’-fluoro ribose. In some embodiments, the synRNA does not comprise a 2’ modified ribose in the ORF at the third nucleoside of a codon adjacent to a modified internucleoside linkage. In some embodiments, the synRNA does not comprise a 2’ modified ribose in the ORF at the third nucleoside of a codon. In some embodiments, the synRNA does not comprise a 2’ modified ribose in the ORF. a. Exemplary SynRNA Structures The present disclosure is based, at least in part, on the surprising and advantageous finding that particular chemical modifications, when used in a precise location within a desired nucleic acid molecule, engender resistance to enzymatic and chemical degradation, while retaining the ability of the ribosome to translate the nucleic acid into protein product. For example, in some embodiments, a nucleic acid molecules of the disclosure is a synRNA that comprises at least one codon of Formula SYN-I: -L1-B1-L2-B2-L3-B3-L4- (SYN-I) wherein: each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; each of B1and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside; B2is an unmodified nucleoside, a 2’ modified nucleoside, or a nucleobase-modified nucleoside; and (i) at least one of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) at least one of B1and B3is a 2’ modified nucleoside, or (iii) B2is a 2’ modified nucleoside or a nucleobase-modified nucleoside; further wherein: when B1is a 2’ modified nucleoside, (i) at least one of B2and B3is a modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B2is a 2’ modified nucleoside, (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B2is a nucleobase-modified nucleoside, (i) B1and B3are unmodified nucleosides, or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B3is a 2’ modified nucleoside, (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; and when one or more of L1, L2, L3, and L4is a modified internucleoside linkage, (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, (iv) the 5’ UTR, 3’ UTR, or PATENT ATTORNEY DOCKET NO.50858-153WO4 poly-A region comprises a 2’ modified nucleoside, or (v) the modified internucleoside linkage is . In some embodiments of Formula SYN-I: each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; each of B1, B2, and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside; and (i) at least one of L1, L2, L3, and L4is a modified internucleoside linkage or (ii) at least one of B1, B2, and B3is a 2’ modified nucleoside; further wherein: when B1is a 2’ modified nucleoside, (i) at least one of B2and B3is a modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B2is a 2’ modified nucleoside, (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B3is a 2’ modified nucleoside, (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; and when one or more of L1, L2, L3, and L4is a modified internucleoside linkage, (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, or (iv) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, B1is a 2’ modified nucleoside, and (i) at least one of B2and B3is a 2’ modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, B2is a 2’ modified nucleoside, and (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, B3is a 2’ modified nucleoside, and (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, L1, L2, L3, or L4is a modified internucleoside linkage, and (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, or (iv) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside. In some embodiments, the synRNA comprises a 2’ modified nucleoside in the 5’ UTR. For example, each nucleoside in the 5’ UTR may be a 2’ modified nucleoside. In some embodiments, the synRNA comprises a 2’ modified nucleoside in the 3’ UTR. For example, each nucleoside in the 3’ UTR may be a 2’ modified nucleoside. In some embodiments, the synRNA comprises a 2’ modified nucleoside in the poly-A region. For example, each nucleoside in the poly-A region may be a 2’ modified nucleoside. In some embodiments, the synRNA comprises a modified internucleoside linkage in the 5’ UTR. PATENT ATTORNEY DOCKET NO.50858-153WO4 For example, each internucleoside linkage in the 5’ UTR may be a modified internucleoside linkage. In some embodiments, the synRNA comprises a modified internucleoside linkage in the 3’ UTR. For example, each internucleoside linkage in the 3’ UTR may be a modified internucleoside linkage. In some embodiments, the synRNA comprises a modified internucleoside linkage in the poly-A region. For example, each internucleoside linkage in the poly-A region may be a modified internucleoside linkage. In some embodiments, each modified internucleoside linkage is, independently, selected from the group consisting of a phosphorothioate, a phosphoroselenate, a boranophosphate, a boranophosphate ester, a hydrogen phosphonate, a phosphoramidate, a phosphorodiamidate, an alkyl phosphonate, an aryl phosphonate, a phosphotriester, a phosphorodithioate, a bridged phosphoramidate, a bridged phosphorothioate, a bridged methylene-phosphonate, and an α-thio phosphate. In some embodiments, each modified internucleoside linkage is a phosphorothioate internucleoside linkage. In some embodiments, one or more of the modified internucleoside linkages comprises the structure: . In some embodiments, each 2’ modified nucleoside is, independently, a nucleoside comprising a 2’ ribose modification selected from the group consisting of a 2’-deoxyribose, a 2’-OMe ribose, a 2’-O- methoxyethyl ribose (2’-MOE), a 2’-F ribose, a 2’-NH2 ribose, a 2’fluoroarabino ribose (FANA), a locked nucleic acid (LNA), and a 4’-S ribose. In some embodiments, the 2’ ribose modification is a 2’-O-methyl ribose or a 2’-fluoro ribose. In some embodiments, the poly-A region is bound, at its 3’ end, to a modified nucleoside. In some embodiments, the modified nucleoside bound to the poly-A region is selected from the group consisting of an inverted deoxythymidine, a 2’-deoxynucleoside, a 3’-deoxynucleoside, a 2’,3’-dideoxynucleoside, a 2’- O-methylnucleoside, a 3’-O-methylnucleoside, a 3’-O-ethyl-nucleoside, 3’-arabinoside, an L-nucleoside, an alpha-thio-2’-O-methyl-adenosine, 2’-fluoro-adenosine, an arabino-adenosine, a hexitol-adenosine, an LNA-adenosine, a PNA-adenosine, and a 3’-azido-2´,3´-dideoxyadenosine. In some embodiments, the modified nucleoside is an inverted deoxythymidine. In some embodiments, the codon of SYN-I has the structure of Formula SYN-II: -L1-B1-L2-B2-L3-B3-L4- wherein: each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage, optionally wherein the modified internucleoside linkage is selected from the group consisting of a phosphorothioate, a phosphoroselenate, a boranophosphate, a boranophosphate ester, a hydrogen phosphonate, a phosphoramidate, a phosphorodiamidate, an alkyl phosphonate, an aryl phosphonate, a phosphotriester, a phosphorodithioate, a bridged phosphoramidate, a bridged phosphorothioate, a bridged methylene-phosphonate, and an α-thio phosphate; each of B1, B2, and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside; and PATENT ATTORNEY DOCKET NO.50858-153WO4 at least one of B1, B2, and B3is a 2’ modified nucleoside, optionally wherein the 2’ modified nucleoside comprises a 2’ ribose modification selected from the group consisting of a 2’-deoxyribose, a 2’-OMe ribose, a 2’-MOE, a 2’-F ribose, a 2’-NH2 ribose, a 2’FANA, an LNA, and a 4’-S ribose. In some embodiments of Formula SYN-II, B1is a 2’-modified nucleoside. In some embodiments, B1is a 2’-fluoro nucleoside. In some embodiments, B1is an LNA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-III: -L1-F-L2-B2-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B2and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-IV: -L1-B1-L2-B2-L3-F-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-V: -L1-F-L2-B2-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; B2is an unmodified nucleoside; and B3is a 2’ modified nucleoside. In some embodiments, B3is a 2’-fluoro nucleoside. In some embodiments, B3is an LNA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-VI: -S-B1-L2-B2-L3-B3-S- wherein: S is a phosphorothioate internucleoside linkage; each of L2and L3is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1, B2, and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-VII: -S-B1-L2-B2-L3- B3-S- wherein: S is a phosphorothioate internucleoside linkage; each of L2and L3is an unmodified internucleoside linkage; and each of B1, B2, and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-VIII: -L1-B1-L2-B2-L3-R-L4- PATENT ATTORNEY DOCKET NO.50858-153WO4 wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and R is an arabinose nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-IX: -L1-N-L2-B2-L3-B3-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B2and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-X: -L1-N-L2-B2-L3-B3-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B2and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XI: -L1-B1-L2-F-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XII: -L1-B1-L2-F-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XIII: -L1-B1-L2-N-L3-B3-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1and B3is, independently, an unmodified nucleoside or a modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XIV: -L1-B1-L2-N-L3-B3-L4- wherein: N is an LNA nucleoside; PATENT ATTORNEY DOCKET NO.50858-153WO4 each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XV: -L1-B1-L2-B2-L3-N-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1and B2is, independently, an unmodified nucleoside or a modified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XVI: -L1-B1-L2-B2-L3-N-L4- wherein: N is an LNA nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XVII: -L1-B1-L2-B2-L3-M-L4- wherein: M is a 2’-methoxy nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XVIII: -L1-B1-S-B2-L3- B3-L4- wherein: S is a phosphorothioate internucleoside linkage; each of L1, L3and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XIX: -L1-B1-L2-B2-S- B3-L4- wherein: S is a phosphorothioate internucleoside linkage; each of L1, L2and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XX: -S-B1-L2-F-L3-B3-S- wherein: S is a phosphorothioate internucleoside linkage; F is a 2’-fluoro nucleoside; each of L2and L3is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B1and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXI: -S-B1-L2-F-L3-B3-S- wherein: S is a phosphorothioate internucleoside linkage; F is a 2’-fluoro nucleoside; each of L2and L3is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXII: -L1-B1-L2-B2-S-M-L4- wherein: M is a 2’-methoxy nucleoside; S is a phosphorothioate internucleoside linkage; each of L1, L2, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXIII: -L1-B1-L2-B2-L3-M-S- wherein: each of L1, L2, and L3is a phosphodiester internucleoside linkage; S is a phosphorothioate internucleoside linkage; each of B1and B2is an unmodified nucleoside; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXIV: -L1-B1-L2-B2-L3-B3-Z- wherein: each of L1, L2, and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure: . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXV: -L1-B1-Z-B2-L3-B3-L4- wherein: each of L1, L3, and L4is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure: PATENT ATTORNEY DOCKET NO.50858-153WO4 . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXVI: -L1-B1-Z-B2-L3-B3-Z- wherein: each of L1and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure: . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXVII: -L1-F-L2-B2-L3-M-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; B2is an unmodified nucleoside; M is a 2’-methoxy nucleoside; and F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXVIII: -L1-M-L2-M-L3-M-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXIX: -S-M-S-M-S-M-L4- wherein: L4is a phosphodiester internucleoside linkage; S is a phosphorothioate internucleoside linkage; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXX: -L1-M-L2-B2-L3-B3-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B2and B3is an unmodified nucleoside; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXI: -L1-B1-L2-M-L3-B3-L4- wherein: PATENT ATTORNEY DOCKET NO.50858-153WO4 each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B1and B3is an unmodified nucleoside; and M is a 2’-methoxy nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXII: -L1-B1-L2-B2-L3-D-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and D is a deoxyribonucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXIII: -L1-D-L2-D-L3-D-L4- wherein: each of L1, L2, L3, and L4is a phosphodiester internucleoside linkage; and D is a deoxyribonucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXIV: -L1-B1-L2-m6A-L3-B3-L4- wherein: m6A is N6-methyl-adenosine; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXV: -L1-F-L2-B2-S-B3-L4- wherein: each of L1, L2, and L4are phosphorothioate internucleoside linkages; each of B2and B3is an unmodified nucleoside; and F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXVI: -S-F-L2-B2-L3-B3-S- wherein: each of L2and L3are phosphorothioate internucleoside linkages; S is a phosphorothioate internucleoside linkage; each of B2and B3is an unmodified nucleoside; and F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXVII: -S-B1-L2-B2-L3-F-S- wherein: each of L2and L3are phosphorothioate internucleoside linkages; S is a phosphorothioate internucleoside linkage; each of B1and B2is an unmodified nucleoside; and F is a 2’-fluoro nucleoside. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXVIII: -S-F-L2-F-L3-B3-S- wherein: each of L2and L3are phosphorothioate internucleoside linkages; S is a phosphorothioate internucleoside linkage; B3is an unmodified nucleoside; and each F is a 2’-fluoro nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XXXIX: -L1-FN-L2-B2-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B2and B3is an unmodified nucleoside; and FN is a 2’-FANA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XL: -L1-B1-L2-FN-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B3is an unmodified nucleoside; and FN is a 2’-FANA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLI: -L1-B1-L2- B2-L3-FN-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and FN is a 2’-FANA nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLII: -L1-N-L2-B2-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B2and B3is an unmodified nucleoside; and N is a 2’-NH2 nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLIII: -L1-B1-L2-N-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B3is an unmodified nucleoside; and N is a 2’-NH2 nucleoside. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLIV: -L1-B1-L2- B2-L3-N-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B1and B2is an unmodified nucleoside; and N is a 2’- NH2 nucleoside. In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLV: -L1-B1-L2-B2-Q-B3-L4- wherein: each of L1, L2and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Q represents a modified internucleoside linkage of the following structure: . In some embodiments, the codon of SYN-I has the structure of Formula SYN-XLVI: -L1-B1-L2-B2-L3-B3-Q- wherein: each of L1, L2, and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Q represents a modified internucleoside linkage of the following structure: . In some embodiments, only one codon in the synRNA has the structure of SYN-I. Alternatively, in some embodiments, the synRNA comprises a plurality of codons having the structure of SYN-I. For example, the synRNA may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or more codons having the structure of SYN-I. In some embodiments, fewer than 1% of the codons in the synRNA have the structure of SYN-I. Alternatively, in some embodiments, between 2% and 100% of the codons in the synRNA have the structure of SYN-I. For example, in some embodiments, at least 2% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 3% of the codons in the synRNA have the structure of SYN-I. In some embodiments, In some embodiments, at least 4% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 5% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 6% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 7% of the codons in the synRNA have the structure of SYN-I. In some PATENT ATTORNEY DOCKET NO.50858-153WO4 embodiments, at least 8% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 9% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 10% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 20% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 30% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 40% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 50% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 60% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 70% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 80% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 90% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 91% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 92% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 93% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 94% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 95% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 96% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 97% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 98% of the codons in the synRNA have the structure of SYN-I. In some embodiments, at least 99% of the codons in the synRNA have the structure of SYN-I. In some embodiments, 100% of the codons in the synRNA have the structure of SYN-I. In some embodiments, the synRNA comprises two consecutive codons that, together, have the structure of Formula SYN-XLVII: -S-F-L2-F-L3-B3-S-B4-L5-F-L6-B6-S- wherein: each S is a phosphorothioate internucleoside linkage; each F is a 2’-fluoro nucleoside; each of L2, L3, L5, and L6is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; and each of B3, B4, and B6is, independently, an unmodified nucleoside or a 2’ modified nucleoside. In some embodiments of Formula SYN- XLVII: each S is a phosphorothioate internucleoside linkage; each of L2, L3, L5, and L6is an unmodified internucleoside linkage; and each of B3, B4, and B6is an unmodified nucleoside. In some embodiments, the synRNA comprises two consecutive codons that, together, have the structure of Formula SYN-XLVIII: -S-F-L2-F-L3-B3-S-F-L5-B5-L6-B6-S wherein: each S is a phosphorothioate internucleoside linkage; each F is a 2’-fluoro nucleoside; each of L2, L3, L5, and L6is an unmodified internucleoside linkage; and PATENT ATTORNEY DOCKET NO.50858-153WO4 each of B3, B5, and B6is an unmodified nucleoside. In some embodiments, the synRNA comprises two consecutive codons that, together, have the structure of Formula SYN-XLIX: -S-F-L2-B2-L3-F-S-B4-L5-F-L6-B6-S wherein: each S is a phosphorothioate internucleoside linkage; each F is a 2’-fluoro nucleoside; each of L2, L3, L5, and L6is an unmodified internucleoside linkage; and each of B2, B4, and B6is an unmodified nucleoside. b. Exemplary Nucleobase Modifications In some embodiments of any of the foregoing formulas, a modified nucleoside, as that term is used above, may contain one or more modifications to the corresponding nucleobase. For example, the modification to the nucleobase may be the only modification in the nucleoside or the modification to the nucleobase may be in addition to a modification at the 2’ position of the ribose portion of the nucleoside. Exemplary non-limiting nucleobase modifications include the presence of an amino group, a thiol group, an alkyl group, a halo group, or any described herein. The alternative nucleotides may by synthesized by any useful method, as described herein (e.g., chemically, enzymatically, or recombinantly to include one or more alternative or alternative nucleosides). In some embodiments, the modified nucleobase is a modified uracil. Exemplary nucleobases and nucleosides having a modified uracil include pseudouridine (ψ), pyridin-4-one ribonucleoside, 5-aza- uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s2U), 4-thio-uridine (s4U), 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho5U), 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridineor 5-bromo-uridine), 3-methyl-uridine (m3U), 5-methoxy-uridine (mo5U), uridine 5-oxyacetic acid (cmo5U), uridine 5-oxyacetic acid methyl ester (mcmo5U), 5-carboxymethyl-uridine (cm5U), 1-carboxymethyl- pseudouridine, 5-carboxyhydroxymethyl-uridine (chm5U), 5-carboxyhydroxymethyl-uridine methyl ester (mchm5U), 5-methoxycarbonylmethyl-uridine (mcm5U), 5-methoxycarbonylmethyl-2-thio-uridine (mcm5s2U), 5-aminomethyl-2-thio-uridine (nm5s2U), 5-methylaminomethyl-uridine (mnm5U), 5- methylaminomethyl-2-thio-uridine (mnm5s2U), 5-methylaminomethyl-2-seleno-uridine (mnm5se2U), 5- carbamoylmethyl-uridine (ncm5U), 5-carboxymethylaminomethyl-uridine (cmnm5U), 5- carboxymethylaminomethyl-2-thio-uridine (cmnm5s2U), 5-propynyl-uridine, 1-propynyl-pseudouridine, 5- taurinomethyl-uridine (τm5U), 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine(τm5s2U), 1- taurinomethyl-4-thio-pseudouridine, 5-methyl-uridine (m5U, i.e., having the nucleobase deoxythymine), 1- methyl-pseudouridine (m1ψ), 5-methyl-2-thio-uridine (m5s2U), 1-methyl-4-thio-pseudouridine (m1s4ψ), 4- thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m3ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1- deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6-dihydrouridine, 5-methyl-dihydrouridine (m5D), 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2- methoxy-uridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1-methyl-pseudouridine, 3-(3-amino-3-carboxypropyl)uridine (acp3U), 1-methyl-3-(3-amino-3- carboxypropyl)pseudouridine (acp3ψ), 5-(isopentenylaminomethyl)uridine (inm5U), 5- (isopentenylaminomethyl)-2-thio-uridine (inm5s2U), α-thio-uridine, 2′-O-methyl-uridine (Um), 5,2′-O- PATENT ATTORNEY DOCKET NO.50858-153WO4 dimethyl-uridine (m5Um), 2′-O-methyl-pseudouridine (ψm), 2-thio-2′-O-methyl-uridine (s2Um), 5- methoxycarbonylmethyl-2′-O-methyl-uridine (mcm5Um), 5-carbamoylmethyl-2′-O-methyl-uridine (ncm5Um), 5-carboxymethylaminomethyl-2′-O-methyl-uridine (cmnm5Um), 3,2′-O-dimethyl-uridine (m3Um), and 5-(isopentenylaminomethyl)-2′-O-methyl-uridine (inm5Um), 1-thio-uridine, deoxythymidine, 2’‐F‐ara‐uridine, 2’‐F‐uridine, 2’‐OH‐ara‐uridine, 5‐(2‐carbomethoxyvinyl) uridine, and 5‐[3‐(1‐E‐ propenylamino)uridine. In preferred embodiments, the nucleic acid is modified to contain 1-methylpseudouridine (m1ψ) in lieu of uridine at each instance. In some embodiments, the modified nucleobase is a modified cytosine. Exemplary nucleobases and nucleosides having a modified cytosine include 5-aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3- methyl-cytidine (m3C), N4-acetyl-cytidine (ac4C), 5-formyl-cytidine (f5C), N4-methyl-cytidine (m4C), 5- methyl-cytidine (m5C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm5C), 1-methyl- pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine (s2C), 2-thio-5-methyl- cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza- pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl- zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, lysidine (k2C), α-thio-cytidine, 2′-O- methyl-cytidine (Cm), 5,2′-O-dimethyl-cytidine (m5Cm), N4-acetyl-2′-O-methyl-cytidine (ac4Cm), N4,2′-O- dimethyl-cytidine (m4Cm), 5-formyl-2′-O-methyl-cytidine (f5Cm), N4,N4,2′-O-trimethyl-cytidine (m42Cm), 1- thio-cytidine, 2’‐F‐ara‐cytidine, 2’‐F‐cytidine, and 2’‐OH‐ara‐cytidine. In some embodiments, the modified nucleobase is a modified adenine. Exemplary nucleobases and nucleosides having a modified adenine include 2-amino-purine, 2, 6-diaminopurine, 2-amino-6-halo- purine (e.g., 2-amino-6-chloro-purine), 6-halo-purine (e.g., 6-chloro-purine), 2-amino-6-methyl-purine, 8- azido-adenosine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2- amino-purine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyl-adenosine (m1A), 2-methyl-adenine (m2A), N6-methyl-adenosine (m6A), 2-methylthio-N6-methyl-adenosine (ms2m6A), N6- isopentenyl-adenosine (i6A), 2-methylthio-N6-isopentenyl-adenosine (ms2i6A), N6-(cis- hydroxyisopentenyl)adenosine (io6A), 2-methylthio-N6-(cis-hydroxyisopentenyl)adenosine (ms2io6A), N6- glycinylcarbamoyl-adenosine (g6A), N6-threonylcarbamoyl-adenosine (t6A), N6-methyl-N6- threonylcarbamoyl-adenosine (m6t6A), 2-methylthio-N6-threonylcarbamoyl-adenosine (ms2g6A), N6,N6- dimethyl-adenosine (m62A), N6-hydroxynorvalylcarbamoyl-adenosine (hn6A), 2-methylthio-N6- hydroxynorvalylcarbamoyl-adenosine (ms2hn6A), N6-acetyl-adenosine (ac6A), 7-methyl-adenine, 2- methylthio-adenine, 2-methoxy-adenine, α-thio-adenosine, 2′-O-methyl-adenosine (Am), N6,2′-O- dimethyl-adenosine (m6Am), N6,N6,2′-O-trimethyl-adenosine (m62Am), 1,2′-O-dimethyl-adenosine (m1Am), 2′-O-ribosyladenosine (phosphate) (Ar(p)), 2-amino-N6-methyl-purine, 1-thio-adenosine, 8-azido- adenosine, 2’‐F‐ara‐adenosine, 2’‐F‐adenosine, 2’‐OH‐ara‐adenosine, and N6‐(19‐amino‐ pentaoxanonadecyl)-adenosine. In some embodiments, the modified nucleobase is a modified guanine. Exemplary nucleobases and nucleosides having an alternative guanine include inosine (I), 1-methyl-inosine (m1I), wyosine (imG), methylwyosine (mimG), 4-demethyl-wyosine (imG-14), isowyosine (imG2), wybutosine (yW), peroxywybutosine (o2yW), hydroxywybutosine (OhyW), undermodified hydroxywybutosine (OhyW*), 7- PATENT ATTORNEY DOCKET NO.50858-153WO4 deaza-guanosine, queuosine (Q), epoxyqueuosine (oQ), galactosyl-queuosine (galQ), mannosyl- queuosine (manQ), 7-cyano-7-deaza-guanosine (preQ0), 7-aminomethyl-7-deaza-guanosine (preQ1), archaeosine (G+), 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7- deaza-8-aza-guanosine, 7-methyl-guanosine (m7G), 6-thio-7-methyl-guanosine, 7-methyl-inosine, 6- methoxy-guanosine, 1-methyl-guanosine (m1G), N2-methyl-guanosine (m2G), N2,N2-dimethyl-guanosine (m22G), N2,7-dimethyl-guanosine (m2,7G), N2, N2,7-dimethyl-guanosine (m2,2,7G), 8-oxo-guanosine, 7- methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, N2,N2-dimethyl-6-thio- guanosine, α-thio-guanosine, 2′-O-methyl-guanosine (Gm), N2-methyl-2′-O-methyl-guanosine (m2Gm), N2,N2-dimethyl-2′-O-methyl-guanosine (m22Gm), 1-methyl-2′-O-methyl-guanosine (m1Gm), N2,7- dimethyl-2′-O-methyl-guanosine (m2,7Gm), 2′-O-methyl-inosine (Im), 1,2′-O-dimethyl-inosine (m1Im), 2′-O- ribosylguanosine (phosphate) (Gr(p)) , 1-thio-guanosine, O6-methyl-guanosine, 2’‐F‐ara‐guanosine, and 2’‐F‐guanosine. The nucleobase of the nucleotide can be independently selected from a purine, a pyrimidine, a purine, or pyrimidine analog. For example, the nucleobase can each be independently selected from adenine, cytosine, guanine, uracil, or hypoxanthine. In some embodiments, the nucleobase can also include, for example, naturally-occurring and synthetic derivatives of a base, including pyrazolo[3,4- d]pyrimidines, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2- aminoadenine, 6-methyl, and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7- methyladenine, 8-azaguanine and 8-azaadenine, deazaguanine, 7-deazaguanine, 3-deazaguanine, deazaadenine, 7-deazaadenine, 3-deazaadenine, pyrazolo[3,4-d]pyrimidine, imidazo[1,5-a]1,3,5 triazinones, 9-deazapurines, imidazo[4,5-d]pyrazines, thiazolo[4,5-d]pyrimidines, pyrazin-2-ones, 1,2,4- triazine, pyridazine; and 1,3,5 triazine. When the nucleotides are depicted using the shorthand A, G, C, T or U, each letter refers to the representative base and / or derivatives thereof (e.g., A includes adenine or adenine analogs (e.g., 7-deaza adenine)). In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5- methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-trifluoromethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5- methoxy-uracil, uracil, 5-hydroxymethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-bromo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-iodo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-methoxy- cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-ethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5- phenyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the PATENT ATTORNEY DOCKET NO.50858-153WO4 polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-ethnyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy- uracil, uracil, N4-methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-fluoro-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5- methoxy-uracil, uracil, N4-acetyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, pseudoisocytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-formyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5- aminoallyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uracil, uracil, 5-carboxy-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-trifluoromethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-hydroxymethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-bromo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-iodo-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1- methyl-pseudouracil, uracil, 5-methoxy-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-ethyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-phenyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-ethnyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, N4-methyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1- methyl-pseudouracil, uracil, 5-fluoro-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, N4-acetyl- cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, pseudoisocytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-formyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouracil, uracil, 5-aminoallyl-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 1- methyl-pseudouracil, uracil, 5-carboxy-cytosine, and cytosine as the only uracils and cytosines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5- methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the PATENT ATTORNEY DOCKET NO.50858-153WO4 polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-trifluoromethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5- methoxy-uridine, uridine, 5-hydroxymethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-bromo- cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-iodo-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-methoxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-ethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5- methoxy-uridine, uridine, 5-phenyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-ethnyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, N4-methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-fluoro-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, N4-acetyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5- methoxy-uridine, uridine, pseudoisocytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-formyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-aminoallyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 5-methoxy-uridine, uridine, 5-carboxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-trifluoromethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-hydroxymethyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-bromo-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-iodo-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1- methyl-pseudouridine, uridine, 5-methoxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-ethyl- cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-phenyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-ethnyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, N4-methyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1- PATENT ATTORNEY DOCKET NO.50858-153WO4 methyl-pseudouridine, uridine, 5-fluoro-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, N4-acetyl- cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, pseudoisocytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl- pseudouridine, uridine, 5-formyl-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-aminoallyl- cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain 1-methyl-pseudouridine, uridine, 5-carboxy-cytidine, and cytidine as the only uridines and cytidines. In some embodiments, the polynucleotides of the invention contain the uracil of one of the nucleosides of Table 2 and uracil as the only uracils. In other embodiments, the polynucleotides of the invention contain a uridine of Table 2 and uridine as the only uridines. Table 2. Exemplary modified uridine nucleosides PATENT ATTORNEY DOCKET NO.50858-153WO4 PATENT ATTORNEY DOCKET NO.50858-153WO4 PATENT ATTORNEY DOCKET NO.50858-153WO4 PATENT ATTORNEY DOCKET NO.50858-153WO4 PATENT ATTORNEY DOCKET NO.50858-153WO4 PATENT ATTORNEY DOCKET NO.50858-153WO4 PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the polynucleotides of the invention contain the cytosine of one of the nucleosides of Table 3 and cytosine as the only cytosines. In other embodiments, the polynucleotides of the invention contain a cytidine of Table 3 and cytidine as the only cytidines. Table 3. Exemplary modified cytidine nucleosides PATENT ATTORNEY DOCKET NO.50858-153WO4 c. Exemplary Modifications at the 2’ Position of a Ribose Modified nucleosides of the disclosure include 2’-modifide nucleosides, which are nucleosides that contain structural changes at the 2’ position of the ribose unit within the nucleoside core structure. Non-limiting examples of 2’-modified ribose moieties that may be incorporated into the nucleic acid molecules of the disclosure include a 2’-deoxyribose, a 2’-OMe ribose, a 2’-MOE ribose, a 2’-F ribose, a 2’-NH2 ribose, a FANA, and an LNA. In some embodiments, the 2’ modified ribose is a 2’-O-methyl ribose. In some embodiments, the 2’ modified ribose is a 2’-fluoro ribose. PATENT ATTORNEY DOCKET NO.50858-153WO4 d. Exemplary Modified Internucleoside Linkages Modified nucleotides of the disclosure, which may be incorporated into a polynucleotide molecule, can be altered on the internucleoside linkage (e.g., phosphate backbone). Herein, in the context of the polynucleotide backbone, the phrases “phosphate” and “phosphodiester” are used interchangeably. Backbone phosphate groups can be altered by replacing one or more of the oxygen atoms with a different substituent. The alternative nucleosides and nucleotides can include the wholesale replacement of an unaltered phosphate moiety with another internucleoside linkage as described herein. Examples of alternative phosphate groups include, but are not limited to, phosphorothioate, phosphoroselenates, boranophosphates, boranophosphate esters, hydrogen phosphonates, phosphoramidates, phosphorodiamidates, alkyl or aryl phosphonates, and phosphotriesters. Phosphorodithioates have both non-linking oxygens replaced by sulfur. The phosphate linker can also be altered by the replacement of a linking oxygen with nitrogen (bridged phosphoramidates), sulfur (bridged phosphorothioates), and carbon (bridged methylene-phosphonates). The alternative nucleosides and nucleotides can include the replacement of one or more of the non-bridging oxygens with a borane moiety (BH3), sulfur (thio), methyl, ethyl and / or methoxy. As a non- limiting example, two non-bridging oxygens at the same position (e.g., the alpha (α), beta (β) or gamma (γ) position) can be replaced with a sulfur (thio) and a methoxy. The replacement of one or more of the oxygen atoms at the α position of the phosphate moiety (e.g., α-thio phosphate) is provided to confer stability (such as against exonucleases and endonucleases) to RNA and DNA through the unnatural phosphorothioate backbone linkages. Phosphorothioate DNA and RNA have increased nuclease resistance and subsequently a longer half-life in a cellular environment. While not wishing to be bound by theory, phosphorothioate linked polynucleotide molecules are expected to also reduce the innate immune response through weaker binding / activation of cellular innate immune molecules. In specific embodiments, an alternative nucleoside includes an alpha-thio-nucleoside (e.g., 5′-O- (1-thiophosphate)-adenosine, 5′-O-(1-thiophosphate)-cytidine (α-thio-cytidine), 5′-O-(1-thiophosphate)- guanosine, 5′-O-(1-thiophosphate)-uridine, or 5′-O-(1-thiophosphate)-pseudouridine). Other internucleoside linkages that may be employed according to the present invention, including internucleoside linkages which do not contain a phosphorous atom, are described herein below. 2. Modified 5’ and 3’ Stabilizing Regions The nucleic acid molecules of the disclosure may, e.g., contain a modified 5’ and / or 3’ stabilizing region. For example, in some embodiments, the nucleic acids of the invention include a 5’ and / or 3´- stabilizing region including one or more nucleosides (e.g., 1 to 500 nucleosides such as 1 to 200, 1 to 400, 1 to 10, 5 to 15, 10 to 20, 15 to 25, 20 to 30, 25 to 35, 30 to 40, 35 to 45, 40 to 50, 45 to 65, 50 to 70, 65 to 85, 70 to 90, 85 to 105, 90 to 110, 105 to 135, 120 to 150, 130 to 170, 150 to 200 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 nucleosides). In some embodiments, the 5’ and / or 3´-stabilizing region contains one or more chemically modified nucleosides, such as a nucleoside having an alternative nucleobase, sugar, or backbone (e.g., a PATENT ATTORNEY DOCKET NO.50858-153WO4 2´-deoxynucleoside, a 3´-deoxynucleoside, a 2´,3´-dideoxynucleoside, a 2´-O-methylnucleoside, a 3´-O- methylnucleoside, a 3´-O-ethyl-nucleoside, 3´-arabinoside, an L-nucleoside, alpha-thio-2´-O-methyl- adenosine, 2´-fluoro-adenosine, arabino-adenosine, hexitol-adenosine, LNA-adenosine, PNA-adenosine, inverted deoxythymidine, or 3´-azido-2´,3´-dideoxyadenosine). In some embodiments, the 5’ and / or 3´- stabilizing region includes a plurality of alternative nucleosides. In some embodiments, the 5’ and / or 3’- stabilizing region includes at least one non-nucleoside (e.g., an abasic ribose) at the 5’-terminus, the 3’- terminus, or at an internal position of the 5’ and / or 3’-stabilizing region. In some embodiments, the 5’ and / or 3´-stablizing region consists of one nucleoside (e.g., a 2´- deoxynucleoside, a 3´-deoxynucleoside, a 2´,3´-dideoxynucleoside, a 2´-O-methylnucleoside, a 3´-O- methylnucleoside, a 3´-O-ethyl-nucleoside, 3´-arabinoside, an L-nucleoside, alpha-thio-2´-O-methyl- adenosine, 2´-fluoro-adenosine, arabino-adenosine, hexitol-adenosine, LNA-adenosine, PNA-adenosine, inverted deoxythymidine, or 3´-azido-2´,3´-dideoxyadenosine). In some embodiments, one or more nucleosides in the 5’ and / or 3´-stabilizing region include the structure: Formula SR1 Formula SR2 Formula SR3 Formula SR4 wherein B1is a nucleobase; each U and U’ is, independently, O, S, N(RU)nu, or C(RU)nu, wherein nu is 1 or 2 (e.g., 1 for N(RU)nu and 2 for C(RU)nu) and each RUis, independently, H, halo, or optionally substituted C1-C6 alkyl; each of R1, R1’, R1”, R2, R2’, R2”, R3, R4, and R5is, independently, H, halo, hydroxy, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted amino, azido, optionally substituted C6-C10 aryl; or R3and / or R5can join together with one of R1, R1’, R1”, R2, R2’, or R2”to form together with the carbons to which they are attached an optionally substituted C3-C10 carbocycle or an optionally substituted C3-C9 heterocyclyl; each of m and n is independently, 0, 1, 2, 3, 4, or 5; each of Y1, Y2, and Y3, is, independently, O, S, Se, -NRN1-, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene, wherein RN1is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C6-C10 aryl; and each Y4is, independently, H, hydroxy, protected hydroxy, halo, thiol, boranyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, or optionally substituted amino; and PATENT ATTORNEY DOCKET NO.50858-153WO4 Y5is O, S, Se, optionally substituted C1-C6 alkylene, or optionally substituted C1-C6 heteroalkylene; or is a salt thereof. In some embodiments, the 5’ and / or 3´-stabilizing region includes a plurality of adenosines. In some embodiments, all of the nucleosides of the 5’ and / or 3´-stabilizing region are adenosines. In some embodiments, the 5’ and / or 3´-stabilizing region includes at least one (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) alternative nucleosides (e.g., an L-nucleoside such as L-adenosine, 2´-O-methyl-adenosine, alpha-thio-2´-O-methyl- adenosine, 2´-fluoro-adenosine, arabino-adenosine, hexitol-adenosine, LNA-adenosine, PNA-adenosine, or inverted deoxythymidine). In some embodiments, the alternative nucleoside is an L-adenosine, a 2´-O- methyl-adenosine, or an inverted deoxythymidine. In some embodiments, the 5’ and / or 3´-stabilizing region includes a plurality of alternative nucleosides. In some embodiments, all of the nucleotides in the 3′-stabilizing region are alternative nucleosides. In some embodiments, the 5’ and / or 3´-stabilizing region includes at least two different alternative nucleosides. In some embodiments, at least one alternative nucleoside is 2´-O-methyl-adenosine. In some embodiments, at least one alternative nucleoside is inverted deoxythymidine. In some embodiments, at least one alternative nucleoside is 2´-O-methyl- adenosine, and at least one alternative nucleoside is inverted deoxythymidine. In some embodiments, the stabilizing region includes the structure: Formula SR5 or a salt thereof; wherein each X is, independently O or S; and A represents adenine and T represents thymine. In some embodiments, each X is O. In some embodiments, each X is S. In some embodiments, all of the plurality of alternative nucleosides are the same (e.g., all of the alternative nucleosides are L-adenosine). In some embodiments, the 5’ and / or 3’-stabilizing region includes ten nucleosides. In some embodiments, the 5’ and / or 3’-stabilizing region includes eleven nucleosides. In some embodiments, the 5’ and / or 3’-stabilizing region comprises at least five L- adenosines (e.g., at least ten L-adenosines, or at least twenty L-adenosines). In some embodiments, the 5’ and / or 3’-stabilizing region consists of five L-adenosines. In some embodiments, the 5’ and / or 3’- stabilizing region consists of ten L-adenosines. In some embodiments, the 5’ and / or 3’-stabilizing region consists of twenty L-adenosines. Further examples of 5’ and / or 3’-stabilized regions are known in the art, e.g., as described in International Patent Publication Nos. WO2013 / 103659, WO2017 / 049275, and WO2017 / 049286, the 5’ and / or 3’-stabilized regions of which are herein incorporated by references. In some embodiments, the 5´-terminus of the 3´-stabilizing region is conjugated to the 3´-terminus of the 3´-UTR. In some embodiments, the 5´-terminus of the 3´-stabilizing region is conjugated to the 3´- PATENT ATTORNEY DOCKET NO.50858-153WO4 terminus of the poly-A region. In some embodiments, the 5´-terminus of the 3´-stabilizing region is conjugated to the 3´-terminus of the poly-C region. In some embodiments of any of the foregoing polynucleotides, the 3´-stabilizing region includes the 3´-terminus of the polynucleotide. In some embodiments, the 3´-terminus of the 5´-stabilizing region is conjugated to the 5´-terminus of the 5´-UTR. In some embodiments, the 5´-stabilizing region includes the 5´-terminus of the polynucleotide. In some embodiments, the 5’ and / or 3’-stabilizing tail is conjugated to the remainder of the polynucleotide, e.g., via a phosphate linkage. In some embodiments, the phosphate linkage is a natural phosphate linkage. In some embodiments, the conjugation of the 5’ and / or 3’-stabilizing region and the remainder of the polynucleotide is produced via enzymatic or splint ligation. In some embodiments, the 5’ and / or 3’-stabilizing tail is conjugated to the remainder of the polynucleotide, e.g., via a chemical linkage. In some embodiments, the chemical linkage includes the structure of Formula SR6: Formula SR6 wherein a, b, c, e, f, and g are each, independently, 0 or 1; d is 0, 1, 2, or 3; each of R6, R8, R10, and R12, is, independently, optionally substituted C1-C6 alkylene, optionally substituted C1-C6heteroalkylene, optionally substituted C2-C6alkenylene, optionally substituted C2-C6alkynylene, or optionally substituted C6-C10 arylene, O, S, Se, and NR13; R7and R11are each, independently, carbonyl, thiocarbonyl, sulfonyl, or phosphoryl, wherein, if R7is phosphoryl, -(R9)d- is a bond, and e, f, and g are 0, then at least one of R6or R8is not O; and if R11is phosphoryl, -(R9)d- is a bond, and a, b, and c are 0, then at least one of R10or R12is not O; each R9is optionally substituted C1–C10 alkylene, optionally substituted C2–C10 alkenylene, optionally substituted C2–C10 alkynylene, optionally substituted C2–C10 heterocyclylene, optionally substituted C6–C12 arylene, optionally substituted C2-C100 polyethylene glycolene, or optionally substituted C1–C10heteroalkylene, or a bond linking (R6)a-(R7)b-(R8)cto (R10)e-(R11)f-(R12)g, wherein if -(R9)d- is a bond, then at least one of a, b, c, e, f, or g is 1; and R13is hydrogen, optionally substituted C1–C4 alkyl, optionally substituted C2–C4 alkenyl, optionally substituted C2–C4 alkynyl, optionally substituted C2–C6 heterocyclyl, optionally substituted C6–C12 aryl, or optionally substituted C1–C7heteroalkyl. In some embodiments, the chemical linkage comprises the structure of Formula SR7: Formula SR7 wherein B1is a nucleobase, hydrogen, halo, hydroxy, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, PATENT ATTORNEY DOCKET NO.50858-153WO4 optionally substituted amino, azido, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C2-C9 heterocycle; and R14and R15are each, independently, hydrogen or hydroxy. In some embodiments, the chemical linkage includes the structure: , Further examples of chemical linkages to conjugate 5’ and / or 3’-stabilized regions to the remainder of the polynucleotide are known in the art, e.g., as described in International Patent Publication Nos. WO2017 / 049275 and WO2017 / 049286, the chemical linkers of which are herein incorporated by reference. 3. Poly-A Tails In some embodiments, the polynucleotides of the present disclosure further comprise a poly-A tail. During RNA processing, a long chain of adenine nucleotides (poly-A tail) can be added to a polynucleotide (e.g., an mRNA molecule) in order to increase stability. Immediately after transcription, the 3′ end of the transcript can be cleaved to free a 3′ hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 80 to approximately 250 residues long, including approximately 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 residues long. In some embodiments, the poly-A tail is 100 nucleotides in length. According to the present disclosure, terminal groups on the poly A tail can be incorporated for stabilization. Polynucleotides of the present disclosure can include des-3′ hydroxyl tails. They can also include structural moieties or 2'-O-methyl modifications as taught by Junjie Li, et al. (Current Biology, vol. 15, 1501–1507, August 23, 2005), the contents of which are incorporated herein by reference in its entirety). PATENT ATTORNEY DOCKET NO.50858-153WO4 The polynucleotides of the present disclosure can be designed to encode transcripts with alternative poly-A tail structures including histone mRNA. According to Norbury, "Terminal uridylation has also been detected on human replication-dependent histone mRNAs. The turnover of these mRNAs is thought to be important for the prevention of potentially toxic histone accumulation following the completion or inhibition of chromosomal DNA replication. These mRNAs are distinguished by their lack of a 3ʹ poly(A) tail, the function of which is instead assumed by a stable stem–loop structure and its cognate stem–loop binding protein (SLBP); the latter carries out the same functions as those of PABP on polyadenylated mRNAs" (Norbury, "Cytoplasmic RNA: a case of the tail wagging the dog," Nature Reviews Molecular Cell Biology; AOP, published online 29 August 2013; doi:10.1038 / nrm3645), the contents of which are incorporated herein by reference in its entirety. Unique poly-A tail lengths provide certain advantages to the polynucleotides of the present disclosure. Generally, the length of a poly-A tail, when present, is greater than 30 nucleotides in length. In some embodiments, the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides). In some embodiments, the polynucleotide or region thereof includes from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 2,000 to 3,000, from 2,000 to 2,500, and from 2,500 to 3,000). In some embodiments, the poly-A tail is designed relative to the length of the overall polynucleotide or the length of a particular region of the polynucleotide. This design can be based on the length of a coding region, the length of a particular feature or region or based on the length of the ultimate product expressed from the polynucleotides. In this context, the poly-A tail can be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the polynucleotide or feature thereof. The poly-A tail can also be designed as a fraction of the polynucleotides to which it belongs. In this context, the poly-A tail can be 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the total length of the construct, a construct region or the total length of the construct minus the poly-A tail. Further, engineered binding sites and conjugation of polynucleotides for Poly-A binding protein can enhance expression. Additionally, multiple distinct polynucleotides can be linked together via the PABP (Poly-A binding protein) through the 3′-end using modified nucleotides at the 3′-terminus of the poly-A tail. Transfection experiments can be conducted in relevant cell lines and protein production can be assayed by ELISA at 12hr, 24hr, 48hr, 72hr and day 7 post-transfection. In some embodiments, the polynucleotides of the present disclosure are designed to include a polyA-G Quartet region. The G-quartet is a cyclic hydrogen bonded array of four guanine nucleotides that PATENT ATTORNEY DOCKET NO.50858-153WO4 can be formed by G-rich sequences in both DNA and RNA. In some embodiments, the G-quartet is incorporated at the end of the poly-A tail. The resultant polynucleotide is assayed for stability, protein production and other parameters including half-life at various time points. It has been discovered that the polyA-G quartet results in protein production from an mRNA equivalent to at least 75% of that seen using a poly-A tail of 120 nucleotides alone. In some embodiments, the poly-A tail comprises an alternative nucleoside, e.g., inverted deoxythymidine. Poly-A tails comprising an alternative nucleoside, e.g., inverted deoxythymidine, may be generated as described herein. For instance, mRNA constructs may be modified by ligation to stabilize the poly(A) tail. Ligation may be performed using 0.5-1.5 mg / mL mRNA (5′ Cap1, 3′ A100), 50 mM Tris- HCl pH 7.5, 10 mM MgCl2, 1 mM TCEP, 1000 units / mL T4 RNA Ligase 1, 1 mM ATP, 20% w / v polyethylene glycol 8000, and 5:1 molar ratio of modifying oligo to mRNA. Modifying oligo has a sequence of 5’-phosphate-AAAAAAAAAAAAAAAAAAAA-(inverted deoxythymidine (idT) (SEQ ID NO: 2)) (see below). Ligation reactions are mixed and incubated at room temperature (~22°C) for, e.g., 4 hours. Stable tail mRNA is purified by, e.g., dT purification, reverse phase purification, hydroxyapatite purification, ultrafiltration into water, and sterile filtration. The resulting stable tail-containing mRNAs contain the following structure at the 3’end, starting with the poly-A region: A100- UCUAGAAAAAAAAAAAAAAAAAAAA-inverted deoxythymidine (SEQ ID NO: 3). Modifying oligo to stabilize tail (5’-phosphate-AAAAAAAAAAAAAAAAAAAA-(inverted deoxythymidine) (SEQ ID NO: 2)): In some instances, the poly-A tail comprises A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO: 3). In some instances, the poly-A tail consists of A100-UCUAG-A20-inverted deoxy-thymidine (SEQ ID NO: 3). 4. Lipid Nanoparticle (LNP) Compositions The present disclosure provides LNP compositions that encapsulate a nucleic acid molecule (e.g., synRNA molecule) described herein. The LNPs of the disclosure may confer one or more advantageous properties. The lipid nanoparticle compositions described herein may be used for the delivery of therapeutic and / or prophylactic agents, e.g., mRNAs, to mammalian cells or organs. For example, the lipid nanoparticles described herein have little or no immunogenicity. For example, the lipid compounds disclosed herein have a lower immunogenicity as compared to a reference lipid (e.g., MC3, PATENT ATTORNEY DOCKET NO.50858-153WO4 KC2, or DLinDMA). For example, a formulation comprising a lipid disclosed herein and a therapeutic or prophylactic agent, e.g., mRNA, has an increased therapeutic index as compared to a corresponding formulation which comprises a reference lipid (e.g., MC3, KC2, or DLinDMA) and the same therapeutic or prophylactic agent. In some embodiments, the present application provides pharmaceutical compositions comprising: (a) a delivery agent comprising a lipid nanoparticle; and (b) a polynucleotide comprising a synRNA molecule of the disclosure. a. Lipid Nanoparticles In some embodiments, polynucleotides of the present disclosure are formulated in an LNP. LNPs according to the present disclosure may comprise: (i) an ionizable lipid (e.g., an ionizable amino lipid); (ii) a sterol or other structural lipid; (iii) a non-cationic helper lipid or phospholipid; and (iv) a PEG-modified lipid. In some embodiments, lipid nanoparticles according to the present disclosure further comprise one or more polynucleotides of the present disclosure (e.g., a linear or circular RNA encoding a therapeutic polypeptide, such as a therapeutic polypeptide disclosed herein). The lipid nanoparticles according to the present disclosure can be generated using components, compositions, and methods as are generally known in the art, see for example PCT / US2016 / 052352; PCT / US2016 / 068300; PCT / US2017 / 037551; PCT / US2015 / 027400; PCT / US2016 / 047406; PCT / US2016000129; PCT / US2016 / 014280; PCT / US2016 / 014280; PCT / US2017 / 038426; PCT / US2014 / 027077; PCT / US2014 / 055394; PCT / US2016 / 52117; PCT / US2012 / 069610; PCT / US2017 / 027492; PCT / US2016 / 059575 and PCT / US2016 / 069491 all of which are incorporated by reference herein in their entirety. In some embodiments, the lipid nanoparticle comprises an ionizable cationic lipid (e.g., an ionizable amino lipid) at a content of 20-60 mol.%, 25-60 mol.%, 30-60 mol.%, 35-60 mol.%, 40-60 mol.%, 45-60 mol.%, 20-55 mol.%, 25-55 mol.%, 30-55 mol.%, 35-55 mol.%, 40-55 mol.%, 45-55 mol.%, 20-50 mol.%, 25-50 mol.%, 30-50 mol.%, 35-50 mol.%, or 40-50 mol.%. For example, the lipid nanoparticle may comprise an ionizable cationic lipid (e.g., an ionizable amino lipid) at a content of 40-50 mol.%, 45-50 mol.%, 45-46 mol.%, 46-47 mol.%, 47-48 mol.%, 48-49 mol.%, or 49-50 mol.%, for example about 45 mol.%, about 45.5 mol.%, about 46 mol.%, about 46.5 mol.%, about 47 mol.%, about 47.5 mol.%, about 48 mol.%, about 48.5 mol.%, about 49 mol.%, or about 49.5 mol.% ionizable cationic lipid (e.g., an ionizable amino lipid). In some embodiments, the lipid nanoparticle comprises a non-cationic helper lipid or phospholipid at a content of 5-25 mol.%. For example, the lipid nanoparticle may comprise a non-cationic helper lipid or phospholipid at a content of molar ratio of 5-25 mol.%, 5-20 mol.%, 5-15 mol.%, 10-25 mol.%, 10-20 mol.%, 10-15 mol.%, 5-6 mol.%, 6-7 mol.%, 7-8 mol.%, 8-9 mol.%, 9-10 mol.%, 10-11 mol.%, 11-12 mol.%, 12-13 mol.%, 13-14 mol.%, 14-15 mol.%, 10-14 mol.%, 10-13 mol.%, 10-12 mol.%, 10-11 mol.%, 9-15 mol.%, 9-14 mol.%, 9-13 mol.%, 9-12 mol.%, or 9-11 mol.% non-cationic lipid. In some embodiments, the lipid nanoparticle comprises a sterol or other structural lipid at a content molar ratio of 25-55 mol.%, 25-50 mol.%, 25-45 mol.%, 25-40 mol.%, 25-35 mol.%, 30-55 mol.%, 30-50 mol.%, 30-45 mol.%, 30-40 mol.%, 30-35 mol.%, 35-55 mol.%, 35-50 mol.%, 35-45 mol.%, 35-40 mol.%, 25-30 mol.%, 30-35 mol.%, 25-28 mol.%, 28-30 mol.%, 30-33 mol.%, 35-38 mol.%, 38-40 mol.%, PATENT ATTORNEY DOCKET NO.50858-153WO4 36-40 mol.%, 37-40 mol.%, 38-40 mol.%, 38-39 mol.%, 36-40 mol.%, 37-40 mol.%, 36-39 mol.%, or 37- 39 mol.%. For example, the lipid nanoparticle may comprise a sterol or other structural lipid at a content of about 30 mol.%, about 30.5 mol.%, about 31.0 mol.%, about 31.5 mol.%, about 32.0 mol.%, about 32.5 mol.%, about 33.0 mol.%, about 33.5 mol.%, about 34.0 mol.%, about 34.5 mol.%, about 35.0 mol.%, about 35.5 mol.%, about 36.0 mol.%, about 36.5 mol.%, about 37.0 mol.%, about 37.5 mol.%, about 38.0 mol.%, about 38.5 mol.%, about 39.0 mol.%, about 39.5 mol.%, about 40.0 mol.%, about 40.5 mol.%, about 41.0 mol.%, about 41.5 mol.%, about 42.0 mol.%, about 42.5 mol.%, about 43.0 mol.%, about 43.5 mol.%, about 44.0 mol.%, about 44.5 mol.%, or about 45.0 mol.%. In some embodiments, the lipid nanoparticle comprises a PEG-modified lipid at a content of 0.5- 15 mol.%, 1.0-15 mol.%, 1.5-15 mol.%, 2.0-15 mol.%, 2.5-15 mol.%, 3.0-15 mol.%, 3.5-15 mol.%, 4.0-15 mol.%, 4.5-15 mol.%, 5.0-15 mol.%, 10-15 mol.%, 0.5-10 mol.%, 0.5-5 mol.%, 0.5-4.5 mol.%, 0.5-4.0 mol.%, 0.5-3.5 mol.%, 0.5-3.0 mol.%, 0.5-2.5 mol.%, 0.5-2.0 mol.%, 0.5-1.5 mol.%, 0.5-1.0 mol.%, 1.0-10 mol.%, 1.0-5 mol.%, 1.0-4.5 mol.%, 1.0-4.0 mol.%, 1.0-3.5 mol.%, 1.0-3.0 mol.%, 1.0-2.5 mol.%, 1.0-2.0 mol.%, 1.0-1.5 mol.%, 1.5-5.0 mol.%, 1.5-4.5 mol.%, 1.5-4.0 mol.%, 1.5-3.5 mol.%, 1.5-3.0 mol.%, 1.5- 2.5 mol.%, 1.5-2.0 mol.%, 2.0-5.0 mol.%, 2.0-4.5 mol.%, 2.0-4.0 mol.%, 2.0-3.5 mol.%, 2.0-3.0 mol.%, or 2.0-2.5 mol.%. For example, the lipid nanoparticle may comprise a PEG-modified lipid at a content of a about 0.5 mol.%, about 1.0 mol.%, about 1.5 mol.%, about 2.0 mol.%, about 2.5 mol.%, about 3.0 mol.%, about 3.5 mol.%, about 4.0 mol.%, about 4.5 mol.%, about 5.0 mol.%, about 6.0 mol.%, about 7.0 mol.%, about 8.0 mol.%, about 9.0 mol.%, about 10.0 mol.%, or about 15.0 mol.%. In some embodiments, the lipid nanoparticle comprises: (i) 20 to 60 mol.% ionizable cationic lipid (e.g., ionizable amino lipid), (ii) 25 to 55 mol.% sterol or other structural lipid, (iii) 5 to 25 mol.% non- cationic lipid (e.g., phospholipid), and (iv) 0.5 to 15 mol.% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises: (i) 40 to 50 mol.% ionizable cationic lipid (e.g., ionizable amino lipid), (ii) 30 to 45 mol.% sterol or other structural lipid, (iii) 5 to 15 mol.% non- cationic lipid (e.g., phospholipid), and (iv) 1 to 5 mol.% PEG-modified lipid. In some embodiments, the lipid nanoparticle comprises: (i) 45 to 50 mol.% ionizable cationic lipid (e.g., ionizable amino lipid), (ii) 35 to 45 mol.% sterol or other structural lipid, (iii) 8 to 12 mol.% non- cationic lipid (e.g., phospholipid), and (iv) 1.5 to 3.5 mol.% PEG-modified lipid. In the following sections, “Compounds” numbered with an “I-” prefix (e.g., “Compound I-18,” “Compound I-301,” “Compound II-6,” “Compound I-VI,” etc., indicate specific ionizable lipid compounds. Likewise, compounds numbered with a “P-” prefix (e.g., “Compound P-I,” etc.) indicate a specific PEG- modified lipid compound. b. Ionizable Amino Lipids In some embodiments, the lipid nanoparticle of the present disclosure comprises an ionizable cationic lipid (e.g., an ionizable amino lipid). In some embodiments, the ionizable lipid is a compound of Formula (IL*) PATENT ATTORNEY DOCKET NO.50858-153WO4 or a salt thereof, wherein: R1is -OH, -NRN-C4-10 cycloalkenyl optionally substituted with one or more oxo or -N(RN’RN’’); RNis H or C1-6 alkyl; RN’is H or C1-6 alkyl; RN’’is H or C1-6alkyl; o is 1, 2, 3, or 4; n is 4, 5, 6, 7, or 8; m is 4, 5, 6, 7, or 8; M is -C(=O)-O-* or -O-C(=O)-*, wherein * indicates attachment to R2; M’ is -C(=O)-O-* or -O-C(=O)-*, wherein * indicates attachment to R3; R2is or –(C1-6 alkylene)-(C3-8 cycloalkyl)-C1-6 alkyl; R2ais -H or C1-10 alkyl; R2bis -H or C1-10 alkyl; ; R3ais H or C1-10alkyl; R3bis H or C1-8 alkyl; and R3cis C1-10 alkyl or C2-8 alkenyl. In some embodiments, the ionizable lipid is of Formula (IL**-I): (IL**-I) or a salt thereof, wherein: R1is -OH; o is 2, 3, or 4; n is 4, 5, 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; PATENT ATTORNEY DOCKET NO.50858-153WO4 M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2cis C4-8 alkyl; R3ais C7-10 alkyl; and R3cis C3-5 alkyl. In some embodiments, the ionizable lipid is of Formula (IL**-III): (IL**-III) or a salt thereof, wherein: R1is NRN-C4-10 cycloalkenyl optionally substituted with one or more oxo or -N(RN’RN’’); RNis H; RN’is C1-2alkyl; RN’’is H; o is 2, 3, or 4; n is 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2ais C7-10 alkyl; R2cis C4-6alkyl; R3ais C1-3 alkyl; and R3cis C4-6 alkyl. In some embodiments, the ionizable lipid is of Formula (IL**-IV): (IL**-IV) or a salt thereof, wherein: R1is OH; o is 2, 3, or 4; n is 6, 7, or 8; M is -C(=O)-O-*, wherein * indicates attachment to R2; m is 6, 7, or 8; M’ is -C(=O)-O-*, wherein * indicates attachment to R3; R2bis C3-5 alkyl; PATENT ATTORNEY DOCKET NO.50858-153WO4 R2cis C2-4 alkyl; R3ais C7-10 alkyl; and R3cis C4-6 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-I): (IL*-Ia) or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for variable IL*; and R3ais C1-8 alkyl. In some embodiments, ionizable lipid is of Formula (IL*-Ia): or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula IL*; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-Ia’): (IL*-Ia’) or a salt thereof, wherein: o, M, M’, R2cand R3care as defined for variable IL*; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IIa): (IL*-IIa) or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for Formula IL*; and R3ais C1-8 alkyl. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the ionizable lipid is of Formula (IL*-II’): or a salt thereof, wherein: o, M, M’, R2cand R3care as defined for variable IL*; and R3ais C1-8alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-III): (IL*-III) or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for variable IL*; R2ais a C1-8 alkyl; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IIIa): or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for variable IL*; R2bis a C1-8 alkyl; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IIIa): or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for variable IL*; R2ais a C1-8 alkyl; and PATENT ATTORNEY DOCKET NO.50858-153WO4 R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IIIa’): or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for variable IL*; R2ais a C1-8 alkyl; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IIIb): or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for variable IL*; R2ais a C1-8 alkyl; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IIIb’): or a salt thereof, wherein: R1, o, M, M’, R2c, and R3care as defined for variable IL*; R2ais a C1-8 alkyl; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IV): PATENT ATTORNEY DOCKET NO.50858-153WO4 (IL*-IV) or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for variable IL*; R2bis a C1-8 alkyl; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-IVa): or a salt thereof, wherein: R1, o, m, n, M, M’, R2c, and R3care as defined for variable IL*; R2bis a C1-8alkyl; and R3ais C1-8 alkyl. In some embodiments, the ionizable lipid is of Formula (IL*-Iva’): or a salt thereof, wherein: o, M, M’, R2c, and R3care as defined for variable IL*; R2ais a C1-8 alkyl; and R3ais C1-8 alkyl. Variables o, R1, RN, RN’, RN’’of Ionizable Lipid In some embodiments of the ionizable lipid, o is 1. In some embodiments of the ionizable lipid, o is 2. In some embodiments of the ionizable lipid, o is 3. In some embodiments of the ionizable lipid, o is 4. In some embodiments of the ionizable lipid, R1is -OH. In some embodiments of the ionizable lipid, RNis H. In some embodiments of the ionizable lipid, RNis methyl. In some embodiments of the ionizable lipid, RNis ethyl. In some embodiments of the ionizable lipid, R1is -NRN-cyclobutenyl, wherein the cyclobutenyl is optionally substituted with one or more oxo or -N(RN’RN’’). In some embodiments of the ionizable lipid, RN’is H. In some embodiments of the ionizable lipid, RN’is methyl. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments of the ionizable lipid, RN’is ethyl. In some embodiments of the ionizable lipid, RN’’is H. In some embodiments of the ionizable lipid, RN’’is methyl. In some embodiments of the ionizable lipid, RN’’is ethyl. In some embodiments of the ionizable lipid, RN’is H and RN’’is methyl. In some embodiments of the ionizable lipid, In some embodiments of the ionizable lipid, Variables m and n of the Ionizable Lipid In some embodiments of the ionizable lipid, m is 4. In some embodiments of the ionizable lipid, m is 5. In some embodiments of the ionizable lipid, m is 6. In some embodiments of the ionizable lipid, m is 7. In some embodiments of the ionizable lipid, m is 8. In some embodiments of the ionizable lipid, m is 4. In some embodiments of the ionizable lipid, n is 5. In some embodiments of the ionizable lipid, n is 6. In some embodiments of the ionizable lipid, n is 7. In some embodiments of the ionizable lipid, n is 8. In some embodiments of the ionizable lipid, n is 5 and m is 7. In some embodiments of the ionizable lipid, n is 7 and m is 7. In some embodiments of the ionizable lipid, m is 6 and n is 6. Variables M and M’ In some embodiments of the ionizable lipid, M is -O-C(=O)-*, wherein * indicates attachment to R2. In some embodiments of the ionizable lipid, M is -C(=O)-O-* wherein * indicates attachment to R2. In some embodiments of the ionizable lipid, M’ is -O-C(=O)-*, wherein * indicates attachment to R3. In some embodiments of the ionizable lipid, M’ is -C(=O)-O-* wherein * indicates attachment to R3. In some embodiments of the ionizable lipid, M is -O-C(=O)-*, wherein * indicates attachment to R2, and M’ is -C(=O)-O-* wherein * indicates attachment to R3Variables R2, R2a, R2b, R2c PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments of the ionizable lipid, R2is . In some embodiments of the ionizable lipid, R2ais hydrogen. In some embodiments of the ionizable lipid, R2ais methyl. In some embodiments of the ionizable lipid, R2ais ethyl. In some embodiments of the ionizable lipid, R2ais propyl. In some embodiments of the ionizable lipid, R2ais butyl. In some embodiments of the ionizable lipid, R2ais pentyl. In some embodiments of the ionizable lipid, R2ais hexyl. In some embodiments of the ionizable lipid, R2ais heptyl. In some embodiments of the ionizable lipid, R2ais octyl. In some embodiments of the ionizable lipid, R2bis hydrogen. In some embodiments of the ionizable lipid, R2bis methyl. In some embodiments of the ionizable lipid, R2bis ethyl. In some embodiments of the ionizable lipid, R2bis propyl. In some embodiments of the ionizable lipid, R2bis butyl. In some embodiments of the ionizable lipid, R2bis pentyl. In some embodiments of the ionizable lipid, R2bis hexyl. In some embodiments of the ionizable lipid, R2bis heptyl. In some embodiments of the ionizable lipid, R2bis octyl. In some embodiments of the ionizable lipid, R2ais hydrogen and R2bis hydrogen. In some embodiments of the ionizable lipid, R2ais hexyl and R2bis hydrogen. In some embodiments of the ionizable lipid, R2ais octyl and R2bis hydrogen. In some embodiments of the ionizable lipid, R2ais hydrogen and R2bis butyl. In some embodiments of the ionizable lipid, R2cis methyl. In some embodiments of the ionizable lipid, R2cis ethyl. In some embodiments of the ionizable lipid, R2cis propyl. In some embodiments of the ionizable lipid, R2cis butyl. In some embodiments of the ionizable lipid, R2cis pentyl. In some embodiments of the ionizable lipid, R2cis hexyl. In some embodiments of the ionizable lipid, R2cis heptyl. In some embodiments of the ionizable lipid, R2cis octyl. In some embodiments of the ionizable lipid, R2is –(C1-6 alkylene)-(C3-8 cycloalkyl)-C1-6 alkyl. In some embodiments of the ionizable lipid, R2is –(C1-6 alkylene)-(cyclohexyl)-C1-6 alkyl. In some embodiments of the ionizable lipid, R2is –(C1-6 alkylene)-(cyclopentyl)-C1-6 alkyl. Variables R3, R3a, R3b, and R3cIn some embodiments of the ionizable lipid, In some embodiments of the ionizable lipid, R3ais hydrogen. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments of the ionizable lipid, R3ais methyl. In some embodiments of the ionizable lipid, R3ais ethyl. In some embodiments of the ionizable lipid, R3ais propyl. In some embodiments of the ionizable lipid, R3ais butyl. In some embodiments of the ionizable lipid, R3ais pentyl. In some embodiments of the ionizable lipid, R3ais hexyl. In some embodiments of the ionizable lipid, R3ais heptyl. In some embodiments of the ionizable lipid, R3ais octyl. In some embodiments of the ionizable lipid, R3bis hydrogen. In some embodiments of the ionizable lipid, R3bis methyl. In some embodiments of the ionizable lipid, R3bis ethyl. In some embodiments of the ionizable lipid, R3bis propyl. In some embodiments of the ionizable lipid, R3bis butyl. In some embodiments of the ionizable lipid, R3bis pentyl. In some embodiments of the ionizable lipid, R3bis hexyl. In some embodiments of the ionizable lipid, R3bis heptyl. In some embodiments of the ionizable lipid, R3bis octyl. In some embodiments of the ionizable lipid, R3ais octyl and R3bis hydrogen. In some embodiments of the ionizable lipid, R3ais ethyl and R3bis hydrogen. In some embodiments of the ionizable lipid, R3ais hexyl and R3bis hydrogen. In some embodiments of the ionizable lipid, R3cis methyl. In some embodiments of the ionizable lipid, R3cis ethyl. In some embodiments of the ionizable lipid, R3cis propyl. In some embodiments of the ionizable lipid, R3cis butyl. In some embodiments of the ionizable lipid, R3cis pentyl. In some embodiments of the ionizable lipid, R3cis hexyl. In some embodiments of the ionizable lipid, R3cis heptyl. In some embodiments of the ionizable lipid, R3cis octyl. It is understood that, for an ionizable lipid, variables o, R1, RN, RN’, RN’, m, n, M, M’, R2, R2a, R2b, R2c, R3, R3a, R3b, and R3ccan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables o,.R1, RN, RN’, RN’, m, n, M, M’, R2, R2a, R2b, R2c, R3, R3a, R3b, and R3ccan be combined, where applicable, with any group described herein for one or more of the remainder of variables o, R1, RN, RN’, RN’, m, n, M, M’, R2, R2a, R2b, R2c, R3, R3a, R3b, and R3c. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, the ionizable lipid is a compound selected from: In some embodiments, the ionizable is In some embodiments, the ionizable is Without wishing to be bound by theory, it is understood that an ionizable lipid may have a positive or partial positive charge at physiological pH. Such lipids may be referred to as cationic or ionizable (amino)lipids. Lipids may also be zwitterionic, i.e., neutral molecules having both a positive and a negative charge. c. Phospholipids The lipid composition of the lipid nanoparticle composition disclosed herein can comprise one or more phospholipids, for example, one or more saturated or (poly)unsaturated phospholipids or a combination thereof. In general, phospholipids comprise a phospholipid moiety and one or more fatty acid moieties. PATENT ATTORNEY DOCKET NO.50858-153WO4 A phospholipid moiety can be selected, for example, from the non-limiting group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, 2-lysophosphatidyl choline, and a sphingomyelin. A fatty acid moiety can be selected, for example, from the non-limiting group consisting of lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, erucic acid, phytanoic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid. Particular phospholipids can facilitate fusion to a membrane. For example, a cationic phospholipid can interact with one or more negatively charged phospholipids of a membrane (e.g., a cellular or intracellular membrane). Fusion of a phospholipid to a membrane can allow one or more elements (e.g., a therapeutic agent) of a lipid-containing composition (e.g., LNPs) to pass through the membrane permitting, e.g., delivery of the one or more elements to a target tissue. Non-natural phospholipid species including natural species with modifications and substitutions including branching, oxidation, cyclization, and alkynes are also contemplated. For example, a phospholipid can be functionalized with or cross-linked to one or more alkynes (e.g., an alkenyl group in which one or more double bonds is replaced with a triple bond). Under appropriate reaction conditions, an alkyne group can undergo a copper-catalyzed cycloaddition upon exposure to an azide. Such reactions can be useful in functionalizing a lipid bilayer of a nanoparticle composition to facilitate membrane permeation or cellular recognition or in conjugating a nanoparticle composition to a useful component such as a targeting or imaging moiety (e.g., a dye). Phospholipids include, but are not limited to, glycerophospholipids such as phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols, phosphatidy glycerols, and phosphatidic acids. Phospholipids also include phosphosphingolipid, such as sphingomyelin. In some embodiments, a phospholipid of the present disclosure comprises 1,2-distearoyl-sn- glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-gly cero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2 cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3- phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine,1,2-diarachidonoyl-sn- glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-diphytanoyl-sn- glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2- dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2- diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure is an analog or variant of DSPC. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure is a compound of Formula Lpd (IV): PATENT ATTORNEY DOCKET NO.50858-153WO4 (IV), or a salt thereof, wherein: each R1is independently optionally substituted alkyl; or optionally two R1are joined together with the intervening atoms to form optionally substituted monocyclic carbocyclyl or optionally substituted monocyclic heterocyclyl; or optionally three R1are joined together with the intervening atoms to form optionally substituted bicyclic carbocyclyl or optionally substitute bicyclic heterocyclyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is of the Formula: each instance of L2is independently a bond or optionally substituted C1-6 alkylene, wherein one methylene unit of the optionally substituted C1-6 alkylene is optionally replaced with O, N(RN), S, C(O), - C(O)N(RN), NRNC(O), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, or NRNC(O)N(RN); each instance of R2is independently optionally substituted C1-30 alkyl, optionally substituted C1-30 alkenyl, or optionally substituted C1-30 alkynyl; optionally wherein one or more methylene units of R2are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, C(O), C(O)N(RN), - NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, C(O)S, SC(O), C(=NRN), C(=NRN)N(RN), NRNC(=NRN), NRNC(=NRN)N(RN), C(S), C(S)N(RN), NRNC(S), NRNC(S)N(RN), S(O), - OS(O), S(O)O, OS(O)O, OS(O)2, S(O)2O, OS(O)2O, N(RN)S(O), S(O)N(RN), N(RN)S(O)N(RN), - OS(O)N(RN), N(RN)S(O)O, S(O)2, N(RN)S(O)2, S(O)2N(RN), N(RN)S(O)2N(RN), OS(O)2N(RN), or - N(RN)S(O)2O; each instance of RNis independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Ring B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and p is 1 or 2; provided that the compound is not of the Formula: , wherein each instance of R2is independently unsubstituted alkyl, unsubstituted alkenyl, or unsubstituted alkynyl. In some embodiments, the phospholipids may be one or more of the phospholipids described in U.S. Application No.62 / 520,530. PATENT ATTORNEY DOCKET NO.50858-153WO4 i. Phospholipid Head Modifications In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified phospholipid head (e.g., a modified choline group). In certain embodiments, a phospholipid with a modified head is DSPC, or analog thereof, with a modified quaternary amine. For example, in embodiments of Formula Lpd (IV), at least one of R1is not methyl. In certain embodiments, at least one of R1is not hydrogen or methyl. In certain embodiments, the compound of Formula Lpd (IV) is of one of the following Formulae: or a salt thereof, wherein: each t is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each u is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each v is independently 1, 2, or 3. In certain embodiments, a compound of Formula Lpd (IV) is of Formula Lpd (IV-a): Lpd (IV-a), or a salt thereof. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a cyclic moiety in place of the glyceride moiety. In certain embodiments, a phospholipid useful in the present disclosure is DSPC, or analog thereof, with a cyclic moiety in place of the glyceride moiety. In certain embodiments, the compound of Formula Lpd (IV) is of Formula Lpd (IV-b): , (IV-b), or a salt thereof. ii. Phospholipid Tail Modifications In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified tail. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure is DSPC, or analog thereof, with a modified tail. As described herein, a “modified tail” may be a tail with shorter or longer aliphatic chains, aliphatic chains with branching introduced, aliphatic PATENT ATTORNEY DOCKET NO.50858-153WO4 chains with substituents introduced, aliphatic chains wherein one or more methylenes are replaced by cyclic or heteroatom groups, or any combination thereof. For example, in certain embodiments, the compound of Lpd (IV) is of Formula Lpd (IV-a), or a salt thereof, wherein at least one instance of R2is each instance of R2is optionally substituted C1-30 alkyl, wherein one or more methylene units of R2are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, C(O), C(O)N(RN), - NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, C(O)S, SC(O), C(=NRN), C(=NRN)N(RN), NRNC(=NRN), NRNC(=NRN)N(RN), C(S), C(S)N(RN), NRNC(S), NRNC(S)N(RN), S(O), - OS(O), S(O)O, OS(O)O, OS(O)2, S(O)2O, OS(O)2O, N(RN)S(O), S(O)N(RN), N(RN)S(O)N(RN), - OS(O)N(RN), N(RN)S(O)O, S(O)2, N(RN)S(O)2, S(O)2N(RN), N(RN)S(O)2N(RN), OS(O)2N(RN), or - N(RN)S(O)2O. In certain embodiments, the compound of Formula Lpd (IV) is of Formula Lpd (IV-c): (IV-c), or a salt thereof, wherein: each x is independently an integer between 0-30, inclusive; and each instance is G is independently selected from the group consisting of optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, C(O), C(O)N(RN), NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), - OC(O)O, OC(O)N(RN), NRNC(O)O, C(O)S, SC(O), C(=NRN), C(=NRN)N(RN), NRNC(=NRN), - NRNC(=NRN)N(RN), C(S), C(S)N(RN), NRNC(S), NRNC(S)N(RN), S(O), OS(O), S(O)O, OS(O)O, OS(O)2, S(O)2O, OS(O)2O, N(RN)S(O), S(O)N(RN), N(RN)S(O)N(RN), OS(O)N(RN), N(RN)S(O)O, S(O)2, - N(RN)S(O)2, S(O)2N(RN), N(RN)S(O)2N(RN), OS(O)2N(RN), or N(RN)S(O)2O. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified phosphocholine moiety, wherein the alkyl chain linking the quaternary amine to the phosphoryl group is not ethylene (e.g., n is not 2). Therefore, in certain embodiments, a phospholipid useful or potentially useful in the present disclosure is a compound of Formula Lpd (IV), wherein n is 1, 3, 4, 5, 6, 7, 8, 9, or 10. For example, in certain embodiments, a compound of Formula Lpd (IV) is of one of the following Formulae: , , or a salt thereof. iii. Alternative Lipids In certain embodiments, a phospholipid useful or potentially useful in the present disclosure comprises a modified phosphocholine moiety, wherein the alkyl chain linking the quaternary amine to the PATENT ATTORNEY DOCKET NO.50858-153WO4 phosphoryl group is not ethylene (e.g., n is not 2). Therefore, in certain embodiments, a phospholipid is useful. In certain embodiments, an alternative lipid is used in place of a phospholipid of the present disclosure. In certain embodiments, an alternative lipid of the present disclosure is oleic acid. In certain embodiments, the alternative lipid is one of the following: PATENT ATTORNEY DOCKET NO.50858-153WO4 . d. Structural Lipids The lipid composition of a pharmaceutical composition disclosed herein can comprise one or more structural lipids. As used herein, the term "structural lipid" refers to sterols and also to lipids containing sterol moieties. Incorporation of structural lipids in the lipid nanoparticle may help mitigate aggregation of other lipids in the particle. Structural lipids can be selected from the group including but not limited to, cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, alpha-tocopherol, hopanoids, phytosterols, steroids, and mixtures thereof. In some embodiments, the structural lipid is a sterol. As defined herein, "sterols" are a subgroup of steroids consisting of steroid alcohols. In certain embodiments, the structural lipid is a steroid. In certain embodiments, the structural lipid is cholesterol. In certain embodiments, the structural lipid is an analog of cholesterol. In certain embodiments, the structural lipid is alpha-tocopherol. In some embodiments, the structural lipids may be one or more of the structural lipids described in U.S. Application No.62 / 520,530. e. Polyethylene Glycol (PEG)-Lipids The lipid composition of a pharmaceutical composition disclosed herein can comprise one or more polyethylene glycol (PEG) lipids. As used herein, the term “PEG-lipid” refers to polyethylene glycol (PEG)-modified lipids. Non- limiting examples of PEG-lipids include PEG-modified phosphatidylethanolamine and phosphatidic acid, PEG-ceramide conjugates (e.g., PEG-CerC14 or PEG-CerC20), PEG-modified dialkylamines and PEG- modified 1,2-diacyloxypropan-3-amines. Such lipids are also referred to as PEGylated lipids. For example, a PEG lipid can be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE lipid. In some embodiments, the PEG-lipid includes, but not limited to 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino(polyethylene glycol)] (PEG-DSPE), PEG-disteryl glycerol (PEG-DSG), PEG-dipalmetoleyl, PEG- dioleyl, PEG-distearyl, PEG-diacylglycamide (PEG-DAG), PEG-dipalmitoyl phosphatidylethanolamine (PEG-DPPE), or PEG-l,2-dimyristyloxlpropyl-3-amine (PEG-c-DMA). In some embodiments, the PEG-lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG- modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof. In some embodiments, the lipid moiety of the PEG-lipids includes those having lengths of from about C14 to about C22, preferably from about C14 to about C16. In some embodiments, a PEG moiety, for PATENT ATTORNEY DOCKET NO.50858-153WO4 example an mPEG-NH2, has a size of about 1000, 2000, 5000, 10,000, 15,000 or 20,000 daltons. In some embodiments, the PEG-lipid is PEG2k-DMG. In some embodiments, the lipid nanoparticles described herein can comprise a PEG lipid which is a non-diffusible PEG. Non-limiting examples of non-diffusible PEGs include PEG-DSG and PEG-DSPE. PEG-lipids are known in the art, such as those described in U.S. Patent No.8,158,601 and International Publ. No. WO 2015 / 130584 A2, which are incorporated herein by reference in their entirety. In general, some of the other lipid components (e.g., PEG lipids) of various Formulae, described herein may be synthesized as described International Patent Application No. PCT / US2016 / 000129, filed December 10, 2016, entitled “Compositions and Methods for Delivery of Therapeutic Agents,” which is incorporated by reference in its entirety. The lipid component of a lipid nanoparticle composition may include one or more molecules comprising polyethylene glycol, such as PEG or PEG-modified lipids. Such species may be alternately referred to as PEGylated lipids. A PEG lipid is a lipid modified with polyethylene glycol. A PEG lipid may be selected from the non-limiting group including PEG-modified phosphatidylethanolamines, PEG- modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or a PEG-DSPE lipid. In some embodiments the PEG-modified lipids are a modified form of PEG DMG. PEG-DMG has the following structure: In some embodiments, PEG lipids useful in the present disclosure can be PEGylated lipids described in International Publication No. WO2012099755, the contents of which is herein incorporated by reference in its entirety. Any of these exemplary PEG lipids described herein may be modified to comprise a hydroxyl group on the PEG chain. In certain embodiments, the PEG lipid is a PEG-OH lipid. As generally defined herein, a “PEG-OH lipid” (also referred to herein as “hydroxy-PEGylated lipid”) is a PEGylated lipid having one or more hydroxyl (–OH) groups on the lipid. In certain embodiments, the PEG-OH lipid includes one or more hydroxyl groups on the PEG chain. In certain embodiments, a PEG- OH or hydroxy-PEGylated lipid comprises an –OH group at the terminus of the PEG chain. Each possibility represents a separate embodiment of the present disclosure. In certain embodiments, a PEG lipid useful in the present disclosure is a compound of Formula Lpd (V). Provided herein are compounds of Formula Lpd (V): Lpd (V), or salts thereof, wherein: R3is –ORO; ROis hydrogen, optionally substituted alkyl, or an oxygen protecting group; r is an integer between 1 and 100, inclusive; PATENT ATTORNEY DOCKET NO.50858-153WO4 L1is optionally substituted C1-10 alkylene, wherein at least one methylene of the optionally substituted C1-10 alkylene is independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, O, N(RN), S, C(O), C(O)N(RN), NRNC(O), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, or NRNC(O)N(RN); D is a moiety obtained by click chemistry or a moiety cleavable under physiological conditions; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; A is of the Formula: each instance of L2is independently a bond or optionally substituted C1-6alkylene, wherein one methylene unit of the optionally substituted C1-6 alkylene is optionally replaced with O, N(RN), S, C(O), - C(O)N(RN), NRNC(O), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, or NRNC(O)N(RN); each instance of R2is independently optionally substituted C1-30 alkyl, optionally substituted C1-30 alkenyl, or optionally substituted C1-30 alkynyl; optionally wherein one or more methylene units of R2are independently replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, C(O), C(O)N(RN), - NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, C(O)S, SC(O), C(=NRN), C(=NRN)N(RN), NRNC(=NRN), NRNC(=NRN)N(RN), C(S), C(S)N(RN), NRNC(S), NRNC(S)N(RN), S(O) , - OS(O), S(O)O, OS(O)O, OS(O)2, S(O)2O, OS(O)2O, N(RN)S(O), S(O)N(RN), N(RN)S(O)N(RN), - OS(O)N(RN), N(RN)S(O)O, S(O)2, N(RN)S(O)2, S(O)2N(RN), N(RN)S(O)2N(RN), OS(O)2N(RN), or - N(RN)S(O)2O; each instance of RNis independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group; Ring B is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and p is 1 or 2. In certain embodiments, the compound of Formula Lpd (V) is a PEG-OH lipid (i.e., R3is –ORO, and ROis hydrogen). In certain embodiments, the compound of Formula Lpd (V) is of Formula Lpd (V- OH): Lpd (V-OH), or a salt thereof. In certain embodiments, a PEG lipid useful in the present disclosure is a PEGylated fatty acid. In certain embodiments, a PEG lipid useful in the present disclosure is a compound of Formula Lpd (VI). Provided herein are compounds of Formula Lpd (VI): Lpd (VI), or a salts thereof, wherein: R3is–ORO; ROis hydrogen, optionally substituted alkyl or an oxygen protecting group; PATENT ATTORNEY DOCKET NO.50858-153WO4 r is an integer between 1 and 100, inclusive; R5is optionally substituted C10-40 alkyl, optionally substituted C10-40 alkenyl, or optionally substituted C10-40 alkynyl; and optionally one or more methylene groups of R5are replaced with optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, N(RN), O, S, C(O), C(O)N(RN), NRNC(O), NRNC(O)N(RN), C(O)O, OC(O), OC(O)O, OC(O)N(RN), NRNC(O)O, C(O)S, SC(O), C(=NRN), C(=NRN)N(RN), NRNC(=NRN), - NRNC(=NRN)N(RN), C(S), C(S)N(RN), NRNC(S), NRNC(S)N(RN), S(O), OS(O), S(O)O, OS(O)O, OS(O)2, S(O)2O, OS(O)2O, N(RN)S(O), S(O)N(RN), N(RN)S(O)N(RN), OS(O)N(RN), N(RN)S(O)O, S(O)2, - N(RN)S(O)2, S(O)2N(RN), N(RN)S(O)2N(RN), OS(O)2N(RN), or N(RN)S(O)2O; and each instance of RNis independently hydrogen, optionally substituted alkyl, or a nitrogen protecting group. In certain embodiments, the compound of Formula Lpd (VI) is of Formula Lpd (VI-OH): (VI-OH), or a salt thereof. In some embodiments, r is 45. In yet other embodiments the compound of Formula Lpd (VI) is: . or a salt thereof. In one embodiment, r is 40-50. In some embodiments, the compound of Formula Lpd (VI) is (Compound P-I). In some aspects, the lipid composition of the pharmaceutical compositions disclosed herein does not comprise a PEG-lipid. In some embodiments, the PEG-lipids may be one or more of the PEG lipids described in U.S. Application No.62 / 520,530. In some embodiments, a PEG lipid of the present disclosure comprises a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG- modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof. In some embodiments, the PEG-modified lipid is PEG-DMG, PEG-c-DOMG (also referred to as PEG-DOMG), PEG-DSG and / or PEG-DPG. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of any of Formula Lpd I, Lpd II or Lpd III, a phospholipid comprising DSPC, a structural lipid, and a PEG lipid comprising PEG-DMG. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of any of Formula Lpd I, Lpd II or Lpd III, a phospholipid comprising DSPC, a structural lipid, and a PEG lipid comprising a compound having Formula Lpd VI. PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of Formula Lpd I, Lpd II or Lpd III, a phospholipid comprising a compound having Formula Lpd IV, a structural lipid, and the PEG lipid comprising a compound having Formula Lpd V or Lpd VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of Formula Lpd I, Lpd II or Lpd III, a phospholipid comprising a compound having Formula Lpd IV, a structural lipid, and the PEG lipid comprising a compound having Formula Lpd V or Lpd VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of Formula Lpd I, Lpd II or Lpd III, a phospholipid having Formula Lpd IV, a structural lipid, and a PEG lipid comprising a compound having Formula Lpd VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of , and an alternative lipid comprising oleic acid. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of , an alternative lipid comprising oleic acid, a structural lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula Lpd VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of a phospholipid comprising DOPE, a structural lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula Lpd VI. In some embodiments, a LNP of the present disclosure comprises an ionizable cationic lipid of PATENT ATTORNEY DOCKET NO.50858-153WO4 , a phospholipid comprising DOPE, a structural lipid comprising cholesterol, and a PEG lipid comprising a compound having Formula Lpd VI. In some embodiments, a LNP of the present disclosure comprises an N:P ratio of from about 2:1 to about 30:1. In some embodiments, a LNP of the present disclosure comprises an N:P ratio of about 6:1. In some embodiments, a LNP of the present disclosure comprises an N:P ratio of about 3:1. In some embodiments, a LNP of the present disclosure comprises a wt / wt ratio of the ionizable cationic lipid component to the RNA of from about 10:1 to about 100:1. In some embodiments, a LNP of the present disclosure comprises a wt / wt ratio of the ionizable cationic lipid component to the RNA of about 20:1. In some embodiments, a LNP of the present disclosure comprises a wt / wt ratio of the ionizable cationic lipid component to the RNA of about 10:1. In some embodiments, a LNP of the present disclosure has a mean diameter from about 50nm to about 150nm. In some embodiments, a LNP of the present disclosure has a mean diameter from about 70nm to about 120nm. For the avoidance of doubt, as used herein, alkyl, alkenyl, and cyclyl (e.g., carbocyclyl and heterocyclyl) groups may be optionally substituted unless otherwise specified. Optional substituents may be selected from the group consisting of, but are not limited to, a halogen atom (e.g., a chloride, bromide, fluoride, or iodide group), a carboxylic acid (e.g., C(O)OH), an alcohol (e.g., a hydroxyl, OH), an ester (e.g., C(O)OR OC(O)R), an aldehyde (e.g., C(O)H), a carbonyl (e.g., C(O)R, alternatively represented by C=O), an acyl halide (e.g., C(O)X, in which X is a halide selected from bromide, fluoride, chloride, and iodide), a carbonate (e.g., OC(O)OR), an alkoxy (e.g., OR), an acetal (e.g., C(OR)2R"", in which each OR are alkoxy groups that can be the same or different and R"" is an alkyl or alkenyl group), a phosphate (e.g., P(O)43-), a thiol (e.g., SH), a sulfoxide (e.g., S(O)R), a sulfinic acid (e.g., S(O)OH), a sulfonic acid (e.g., S(O)2OH), a thial (e.g., C(S)H), a sulfate (e.g., S(O)42-), a sulfonyl (e.g., S(O)2 ), an amide (e.g., C(O)NR2, or N(R)C(O)R), an azido (e.g., N3), a nitro (e.g., NO2), a cyano (e.g., CN), an isocyano (e.g., NC), an acyloxy (e.g., OC(O)R), an amino (e.g., NR2, NRH, or NH2), a carbamoyl (e.g., OC(O)NR2, OC(O)NRH, or OC(O)NH2), a sulfonamide (e.g., S(O)2NR2, S(O)2NRH, S(O)2NH2, N(R)S(O)2R, N(H)S(O)2R, N(R)S(O)2H, or N(H)S(O)2H), an alkyl group, an alkenyl group, and a cyclyl (e.g., carbocyclyl or heterocyclyl) group. In any of the preceding, R is an alkyl or alkenyl group, as defined herein. In some embodiments, the substituent groups themselves may be further substituted with, for example, one, two, three, four, five, or six substituents as defined herein. For example, a C1-6 alkyl group may be further substituted with one, two, three, four, five, or six substituents as described herein. PATENT ATTORNEY DOCKET NO.50858-153WO4 f. Other Lipid Composition Components The lipid composition of a pharmaceutical composition disclosed herein can include one or more components in addition to those described above. For example, the lipid composition can include one or more permeability enhancer molecules, carbohydrates, polymers, surface altering agents (e.g., surfactants), or other components. For example, a permeability enhancer molecule can be a molecule described by U.S. Patent Application Publication No.2005 / 0222064. Carbohydrates can include simple sugars (e.g., glucose) and polysaccharides (e.g., glycogen and derivatives and analogs thereof). A polymer can be included in and / or used to encapsulate or partially encapsulate a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition in lipid nanoparticle form). A polymer can be biodegradable and / or biocompatible. A polymer can be selected from, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, polystyrenes, polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyleneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. The ratio between the lipid composition and the polynucleotide range can be from about 10:1 to about 60:1 (wt / wt). In some embodiments, the ratio between the lipid composition and the polynucleotide can be about 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1 or 60:1 (wt / wt). In some embodiments, the wt / wt ratio of the lipid composition to the polynucleotide encoding a therapeutic agent is about 20:1 or about 15:1. In some embodiments, the pharmaceutical composition disclosed herein can contain more than one polypeptide. For example, a pharmaceutical composition disclosed herein can contain two or more polynucleotides (e.g., RNA, e.g., mRNA). In some embodiments, the lipid nanoparticles described herein can comprise polynucleotides (e.g., mRNA) in a lipid:polynucleotide weight ratio of 5:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1 or 70:1, or a range or any of these ratios such as, but not limited to, 5:1 to about 10:1, from about 5:1 to about 15:1, from about 5:1 to about 20:1, from about 5:1 to about 25:1, from about 5:1 to about 30:1, from about 5:1 to about 35:1, from about 5:1 to about 40:1, from about 5:1 to about 45:1, from about 5:1 to about 50:1, from about 5:1 to about 55:1, from about 5:1 to about 60:1, from about 5:1 to about 70:1, from about 10:1 to about 15:1, from about 10:1 to about 20:1, from about 10:1 to about 25:1, from about 10:1 to about 30:1, from about 10:1 to about 35:1, from about 10:1 to about 40:1, from about 10:1 to about 45:1, from about 10:1 to about 50:1, from about 10:1 to about 55:1, from about 10:1 to about 60:1, from about 10:1 to about 70:1, from about 15:1 to about 20:1, from about 15:1 to about 25:1,from about 15:1 to about 30:1, from about 15:1 to about 35:1, from about 15:1 to about 40:1, from about 15:1 to about 45:1, from about 15:1 to about 50:1, from about 15:1 to about 55:1, from about 15:1 to about 60:1 or from about 15:1 to about 70:1. In some embodiments, the lipid nanoparticles described herein can comprise the polynucleotide in a concentration from approximately 0.1 mg / ml to 2 mg / ml such as, but not limited to, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 PATENT ATTORNEY DOCKET NO.50858-153WO4 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml or greater than 2.0 mg / ml. g. Exemplary Nanoparticle Compositions In some embodiments, the pharmaceutical compositions disclosed herein are formulated as lipid nanoparticles (LNP). Accordingly, the present disclosure also provides nanoparticle compositions comprising (i) a lipid composition comprising a delivery agent such as compound as described herein, and (ii) a synRNA described herein and encoding a polypeptide of interest. In such nanoparticle composition, the lipid composition disclosed herein can encapsulate the synRNA. Nanoparticle compositions are typically sized on the order of micrometers or smaller and can include a lipid bilayer. Nanoparticle compositions encompass lipid nanoparticles (LNPs), liposomes (e.g., lipid vesicles), and lipoplexes. For example, a nanoparticle composition can be a liposome having a lipid bilayer with a diameter of 500 nm or less. Nanoparticle compositions include, for example, lipid nanoparticles (LNPs), liposomes, and lipoplexes. In some embodiments, nanoparticle compositions are vesicles including one or more lipid bilayers. In certain embodiments, a nanoparticle composition includes two or more concentric bilayers separated by aqueous compartments. Lipid bilayers can be functionalized and / or crosslinked to one another. Lipid bilayers can include one or more ligands, proteins, or channels. In some embodiments, a lipid nanoparticle comprises an ionizable amino lipid, a structural lipid, a phospholipid, and mRNA. In some embodiments, the LNP comprises an ionizable amino lipid, a PEG- modified lipid, a sterol and a structural lipid. In some embodiments, the LNP has a molar ratio of about 40-50% ionizable amino lipid; about 5-15% structural lipid; about 30-45% sterol; and about 1-5% PEG- modified lipid. In some embodiments, the lipid nanoparticle comprises 47-49 mol.% ionizable cationic lipid (e.g. ionizable amino lipid, e.g., Compound I-18, Compound I-301, or Compound II-6), 10-12 mol.% non- cationic lipid (e.g., phospholipid, e.g., DSPC), 38-40 mol.% sterol (e.g., cholesterol) or other structural lipid, and 1-3 mol.% PEG-modified lipid (e.g., PEG-DMG or Compound P-I). For instance, in some embodiments, the lipid nanoparticle (“LNP-1”) may comprise the following components at the following molar ratios: (i) 45-50 mol.% Compound I-18 (ii) 35-45 mol.% sterol (e.g., cholesterol); (iii) 8-12 mol.% phospholipid (e.g., DSPC or DOPE); and (iv) 1.5-3.5 mol.% PEG-lipid (e.g., Compound P-I or PEG-DMG). For instance, in some embodiments, the lipid nanoparticle (“LNP-1A”) may comprise the following components at the following molar ratios: (i) 45-50 mol.% Compound I-18 (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% PEG-DMG. For instance, in some embodiments, the lipid nanoparticle (“LNP-1B”) may comprise the following components at the following molar ratios: PATENT ATTORNEY DOCKET NO.50858-153WO4 (i) 45-50 mol.% Compound I-18 (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% Compound P-I. In some embodiments, the lipid nanoparticle (“LNP-2”) may comprise the following: (i) 45-50 mol.% Compound I-301; (ii) 35-45 mol.% sterol (e.g., Cholesterol); (iii) 8-12 mol.% phospholipid (e.g., DSPC or DOPE); and (iv) 1.5-3.5 mol.% PEG-lipid (e.g., Compound P-I or PEG-DMG). In some embodiments, the lipid nanoparticle (“LNP-2A”) may comprise the following: (i) 45-50 mol.% Compound I-301; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% PEG-DMG. For instance, in some embodiments, the lipid nanoparticle (“LNP-2B”) may comprise the following components at the following molar ratios: (i) 45-50 mol.% Compound I-301; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% Compound P-I. In some embodiments, the lipid nanoparticle (“LNP-3”) may comprise the following: (i) 45-50 mol.% Compound II-6; (ii) 35-45 mol.% sterol (e.g., Cholesterol); (iii) 8-12 mol.% phospholipid (e.g., DSPC or DOPE); and (iv) 1.5-3.5 mol.% PEG-lipid (e.g., Compound P-I or PEG-DMG). In some embodiments, the lipid nanoparticle (“LNP-3A”) may comprise the following: (i) 45-50 mol.% Compound II-6; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% PEG-DMG. In some embodiments, the lipid nanoparticle (“LNP-3B”) may comprise the following: (i) 45-50 mol.% Compound II-6; (ii) 35-45 mol.% Cholesterol; (iii) 8-12 mol.% DSPC; and (iv) 1.5-3.5 mol.% Compound P-I. In some embodiments, the LNP has a polydispersity value of less than 0.4. In some embodiments, the LNP has a net neutral charge at a neutral pH. In some embodiments, the LNP has a mean diameter of 50-150 nm. In some embodiments, the LNP has a mean diameter of 80-100 nm. As generally defined herein, the term “lipid” refers to a small molecule that has hydrophobic or amphiphilic properties. Lipids may be naturally occurring or synthetic. Examples of classes of lipids include, but are not limited to, fats, waxes, sterol-containing metabolites, vitamins, fatty acids, PATENT ATTORNEY DOCKET NO.50858-153WO4 glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, polyketides, and prenol lipids. In some instances, the amphiphilic properties of some lipids lead them to form liposomes, vesicles, or membranes in aqueous media. In some embodiments, a lipid nanoparticle (LNP) may comprise an ionizable amino lipid. As used herein, the term “ionizable amino lipid” has its ordinary meaning in the art and may refer to a lipid comprising one or more charged moieties. In some embodiments, an ionizable amino lipid may be positively charged or negatively charged. An ionizable amino lipid may be positively charged, in which case it can be referred to as “cationic lipid”. In certain embodiments, an ionizable amino lipid molecule may comprise an amine group and can be referred to as an ionizable amino lipid. As used herein, a “charged moiety” is a chemical moiety that carries a formal electronic charge, e.g., monovalent (+1, or -1), divalent (+2, or -2), trivalent (+3, or -3), etc. The charged moiety may be anionic (i.e., negatively charged) or cationic (i.e., positively charged). Examples of positively-charged moieties include amine groups (e.g., primary, secondary, and / or tertiary amines), ammonium groups, pyridinium groups, guanidine groups, and imidizolium groups. In a particular embodiment, the charged moieties comprise amine groups. Examples of negatively- charged groups or precursors thereof, include carboxylate groups, sulfonate groups, sulfate groups, phosphonate groups, phosphate groups, hydroxyl groups, and the like. The charge of the charged moiety may vary, in some cases, with the environmental conditions, for example, changes in pH may alter the charge of the moiety, and / or cause the moiety to become charged or uncharged. In general, the charge density of the molecule may be selected as desired. It should be understood that the terms “charged” or “charged moiety” does not refer to a “partial negative charge" or “partial positive charge" on a molecule. The terms “partial negative charge" and “partial positive charge" are given their ordinary meaning in the art. A “partial negative charge" may result when a functional group comprises a bond that becomes polarized such that electron density is pulled toward one atom of the bond, creating a partial negative charge on the atom. Those of ordinary skill in the art will, in general, recognize bonds that can become polarized in this way. The ionizable amino lipid is sometimes referred to in the art as an “ionizable cationic lipid”. In some embodiments, the ionizable amino lipid may have a positively charged hydrophilic head and a hydrophobic tail that are connected via a linker structure. In addition to these, an ionizable amino lipid may also be a lipid including a cyclic amine group. In some embodiments, the ionizable amino lipid may be selected from, but not limited to, an ionizable amino lipid described in International Publication Nos. WO2013086354 and WO2013116126; the contents of each of which are herein incorporated by reference in their entirety. In yet another embodiment, the ionizable amino lipid may be selected from, but not limited to, Formula CLI-CLXXXXII of US Patent No.7,404,969; each of which is herein incorporated by reference in their entirety. In some embodiments, the lipid may be a cleavable lipid such as those described in International Publication No. WO2012170889, herein incorporated by reference in its entirety. In some embodiments, the lipid may be synthesized by methods known in the art and / or as described in International Publication Nos. WO2013086354; the contents of each of which are herein incorporated by reference in their entirety. Nanoparticle compositions can be characterized by a variety of methods. For example, microscopy (e.g., transmission electron microscopy or scanning electron microscopy) can be used to PATENT ATTORNEY DOCKET NO.50858-153WO4 examine the morphology and size distribution of a nanoparticle composition. Dynamic light scattering or potentiometry (e.g., potentiometric titrations) can be used to measure zeta potentials. Dynamic light scattering can also be utilized to determine particle sizes. Instruments such as the Zetasizer Nano ZS (Malvern Instruments Ltd, Malvern, Worcestershire, UK) can also be used to measure multiple characteristics of a nanoparticle composition, such as particle size, polydispersity index, and zeta potential. The size of the nanoparticles can help counter biological reactions such as, but not limited to, inflammation, or can increase the biological effect of the polynucleotide. As used herein, “size” or “mean size” in the context of nanoparticle compositions refers to the mean diameter of a nanoparticle composition. In some embodiments, a polynucleotide of the disclosure is formulated in lipid nanoparticles having a diameter from about 10 to about 100 nm such as, but not limited to, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm, about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm, about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and / or about 90 to about 100 nm. In some embodiments, the nanoparticles have a diameter from about 10 to 500 nm. In some embodiments, the nanoparticle has a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm. In some embodiments, the largest dimension of a nanoparticle composition is 1 µm or shorter (e.g., 1 µm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 175 nm, 150 nm, 125 nm, 100 nm, 75 nm, 50 nm, or shorter). A nanoparticle composition can be relatively homogenous. A polydispersity index can be used to indicate the homogeneity of a nanoparticle composition, e.g., the particle size distribution of the nanoparticle composition. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A nanoparticle composition can have a polydispersity index from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. In some embodiments, the polydispersity index of a nanoparticle composition disclosed herein can be from about 0.10 to about 0.20. The zeta potential of a nanoparticle composition can be used to indicate the electrokinetic potential of the composition. For example, the zeta potential can describe the surface charge of a PATENT ATTORNEY DOCKET NO.50858-153WO4 nanoparticle composition. Nanoparticle compositions with relatively low charges, positive or negative, are generally desirable, as more highly charged species can interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the zeta potential of a nanoparticle composition disclosed herein can be from about -10 mV to about +20 mV, from about -10 mV to about +15 mV, from about 10 mV to about +10 mV, from about -10 mV to about +5 mV, from about -10 mV to about 0 mV, from about - 10 mV to about -5 mV, from about -5 mV to about +20 mV, from about -5 mV to about +15 mV, from about -5 mV to about +10 mV, from about -5 mV to about +5 mV, from about -5 mV to about 0 mV, from about 0 mV to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV to about +15 mV, or from about +5 mV to about +10 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be from about 0 mV to about 100 mV, from about 0 mV to about 90 mV, from about 0 mV to about 80 mV, from about 0 mV to about 70 mV, from about 0 mV to about 60 mV, from about 0 mV to about 50 mV, from about 0 mV to about 40 mV, from about 0 mV to about 30 mV, from about 0 mV to about 20 mV, from about 0 mV to about 10 mV, from about 10 mV to about 100 mV, from about 10 mV to about 90 mV, from about 10 mV to about 80 mV, from about 10 mV to about 70 mV, from about 10 mV to about 60 mV, from about 10 mV to about 50 mV, from about 10 mV to about 40 mV, from about 10 mV to about 30 mV, from about 10 mV to about 20 mV, from about 20 mV to about 100 mV, from about 20 mV to about 90 mV, from about 20 mV to about 80 mV, from about 20 mV to about 70 mV, from about 20 mV to about 60 mV, from about 20 mV to about 50 mV, from about 20 mV to about 40 mV, from about 20 mV to about 30 mV, from about 30 mV to about 100 mV, from about 30 mV to about 90 mV, from about 30 mV to about 80 mV, from about 30 mV to about 70 mV, from about 30 mV to about 60 mV, from about 30 mV to about 50 mV, from about 30 mV to about 40 mV, from about 40 mV to about 100 mV, from about 40 mV to about 90 mV, from about 40 mV to about 80 mV, from about 40 mV to about 70 mV, from about 40 mV to about 60 mV, and from about 40 mV to about 50 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be from about 10 mV to about 50 mV, from about 15 mV to about 45 mV, from about 20 mV to about 40 mV, and from about 25 mV to about 35 mV. In some embodiments, the zeta potential of the lipid nanoparticles can be about 10 mV, about 20 mV, about 30 mV, about 40 mV, about 50 mV, about 60 mV, about 70 mV, about 80 mV, about 90 mV, and about 100 mV. The term “encapsulation efficiency” of a polynucleotide describes the amount of the polynucleotide that is encapsulated by or otherwise associated with a nanoparticle composition after preparation, relative to the initial amount provided. As used herein, “encapsulation” can refer to complete, substantial, or partial enclosure, confinement, surrounding, or encasement. Encapsulation efficiency is desirably high (e.g., close to 100%). The encapsulation efficiency can be measured, for example, by comparing the amount of the polynucleotide in a solution containing the nanoparticle composition before and after breaking up the nanoparticle composition with one or more organic solvents or detergents. Fluorescence can be used to measure the amount of free polynucleotide in a solution. For the nanoparticle compositions described herein, the encapsulation efficiency of a polynucleotide can be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, PATENT ATTORNEY DOCKET NO.50858-153WO4 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency can be at least 80%. In certain embodiments, the encapsulation efficiency can be at least 90%. The amount of a polynucleotide present in a pharmaceutical composition disclosed herein can depend on multiple factors such as the size of the polynucleotide, desired target and / or application, or other properties of the nanoparticle composition as well as on the properties of the polynucleotide. For example, the amount of an mRNA useful in a nanoparticle composition can depend on the size (expressed as length, or molecular mass), sequence, and other characteristics of the mRNA. The relative amounts of a polynucleotide in a nanoparticle composition can also vary. The relative amounts of the lipid composition and the polynucleotide present in a lipid nanoparticle composition of the present disclosure can be optimized according to considerations of efficacy and tolerability. For compositions including an mRNA as a polynucleotide, the N:P ratio can serve as a useful metric. As the N:P ratio of a nanoparticle composition controls both expression and tolerability, nanoparticle compositions with low N:P ratios and strong expression are desirable. N:P ratios vary according to the ratio of lipids to RNA in a nanoparticle composition. In general, a lower N:P ratio is preferred. The one or more RNA, lipids, and amounts thereof can be selected to provide an N:P ratio from about 2:1 to about 30:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1. In certain embodiments, the N:P ratio can be from about 2:1 to about 8:1. In other embodiments, the N:P ratio is from about 5:1 to about 8:1. In certain embodiments, the N:P ratio is between 5:1 and 6:1. In one specific aspect, the N:P ratio is about is about 5.67:1. In addition to providing nanoparticle compositions, the present disclosure also provides methods of producing lipid nanoparticles comprising encapsulating a polynucleotide. Such method comprises using any of the pharmaceutical compositions disclosed herein and producing lipid nanoparticles in accordance with methods of production of lipid nanoparticles known in the art. See, e.g., Wang et al. (2015) “Delivery of oligonucleotides with lipid nanoparticles” Adv. Drug Deliv. Rev.87:68-80; Silva et al. (2015) “Delivery Systems for Biopharmaceuticals. Part I: Nanoparticles and Microparticles” Curr. Pharm. Technol.16: 940-954; Naseri et al. (2015) “Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application” Adv. Pharm. Bull.5:305-13; Silva et al. (2015) “Lipid nanoparticles for the delivery of biopharmaceuticals” Curr. Pharm. Biotechnol.16:291-302, and references cited therein. In some embodiments, the LNP formulations described herein can additionally comprise a permeability enhancer molecule. Non-limiting permeability enhancer molecules are described in U.S. Pub. No. US20050222064, herein incorporated by reference in its entirety. The LNP formulations can further contain a phosphate conjugate. The phosphate conjugate can increase in vivo circulation times and / or increase the targeted delivery of the nanoparticle. Phosphate conjugates can be made by the methods described in, e.g., Intl. Pub. No. WO2013033438 or U.S. Pub. No. US20130196948. The LNP formulation can also contain a polymer conjugate (e.g., a water-soluble conjugate) as described in, e.g., U.S. Pub. Nos. US20130059360, US20130196948, and US20130072709. Each of the references is herein incorporated by reference in its entirety. The LNP formulations can comprise a conjugate to enhance the delivery of nanoparticles of the present disclosure in a subject. Further, the conjugate can inhibit phagocytic clearance of the PATENT ATTORNEY DOCKET NO.50858-153WO4 nanoparticles in a subject. In some embodiments, the conjugate can be a "self" peptide designed from the human membrane protein CD47 (e.g., the "self" particles described by Rodriguez et al, Science 2013 339, 971-975, herein incorporated by reference in its entirety). As shown by Rodriguez et al., the self peptides delayed macrophage-mediated clearance of nanoparticles which enhanced delivery of the nanoparticles. The LNP formulations can comprise a carbohydrate carrier. As a non-limiting example, the carbohydrate carrier can include, but is not limited to, an anhydride-modified phytoglycogen or glycogen- type material, phytoglycogen octenyl succinate, phytoglycogen beta-dextrin, anhydride-modified phytoglycogen beta-dextrin (e.g., Intl. Pub. No. WO2012109121, herein incorporated by reference in its entirety). The LNP formulations can be coated with a surfactant or polymer to improve the delivery of the particle. In some embodiments, the LNP can be coated with a hydrophilic coating such as, but not limited to, PEG coatings and / or coatings that have a neutral surface charge as described in U.S. Pub. No. US20130183244, herein incorporated by reference in its entirety. The LNP formulations can be engineered to alter the surface properties of particles so that the lipid nanoparticles can penetrate the mucosal barrier as described in U.S. Pat. No.8,241,670 or Intl. Pub. No. WO2013110028, each of which is herein incorporated by reference in its entirety. The LNP engineered to penetrate mucus can comprise a polymeric material (i.e., a polymeric core) and / or a polymer-vitamin conjugate and / or a tri-block co-polymer. The polymeric material can include, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, poly(styrenes), polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. LNP engineered to penetrate mucus can also include surface altering agents such as, but not limited to, polynucleotides, anionic proteins (e.g., bovine serum albumin), surfactants (e.g., cationic surfactants such as for example dimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives (e.g., cyclodextrin), nucleic acids, polymers (e.g., heparin, polyethylene glycol and poloxamer), mucolytic agents (e.g., N-acetylcysteine, mugwort, bromelain, papain, clerodendrum, acetylcysteine, bromhexine, carbocisteine, eprazinone, mesna, ambroxol, sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosin β4 dornase alfa, neltenexine, erdosteine) and various DNases including rhDNase. In some embodiments, the mucus penetrating LNP can be a hypotonic formulation comprising a mucosal penetration enhancing coating. The formulation can be hypotonic for the epithelium to which it is being delivered. Non-limiting examples of hypotonic formulations can be found in, e.g., Intl. Pub. No. WO2013110028, herein incorporated by reference in its entirety. In some embodiments, the polynucleotide described herein is formulated as a lipoplex, such as, without limitation, the ATUPLEXTM system, the DACC system, the DBTC system and other siRNA- lipoplex technology from Silence Therapeutics (London, United Kingdom), STEMFECTTM from STEMGENT® (Cambridge, MA), and polyethylenimine (PEI) or protamine-based targeted and non- targeted delivery of nucleic acids (Aleku et al. Cancer Res.200868:9788-9798; Strumberg et al. Int J Clin Pharmacol Ther 201250:76-78; Santel et al., Gene Ther 200613:1222-1234; Santel et al., Gene Ther 200613:1360-1370; Gutbier et al., Pulm Pharmacol. Ther.201023:334-344; Kaufmann et al. Microvasc PATENT ATTORNEY DOCKET NO.50858-153WO4 Res 201080:286-293Weide et al. J Immunother.200932:498-507; Weide et al. J Immunother.2008 31:180-188; Pascolo Expert Opin. Biol. Ther.4:1285-1294; Fotin-Mleczek et al., 2011 J. Immunother. 34:1-15; Song et al., Nature Biotechnol.2005, 23:709-717; Peer et al., Proc Natl Acad Sci U S A.2007 6;104:4095-4100; deFougerolles Hum Gene Ther.200819:125-132; all of which are incorporated herein by reference in its entirety). In some embodiments, the polynucleotides described herein are formulated as a solid lipid nanoparticle (SLN), which can be spherical with an average diameter between 10 to 1000 nm. SLNs possess a solid lipid core matrix that can solubilize lipophilic molecules and can be stabilized with surfactants and / or emulsifiers. Exemplary SLNs can be those as described in Intl. Pub. No. WO2013105101, herein incorporated by reference in its entirety. In some embodiments, the polynucleotides described herein can be formulated for controlled release and / or targeted delivery. As used herein, "controlled release" refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome. In some embodiments, the polynucleotides can be encapsulated into a delivery agent described herein and / or known in the art for controlled release and / or targeted delivery. As used herein, the term "encapsulate" means to enclose, surround or encase. As it relates to the formulation of the compounds of the present disclosure, encapsulation can be substantial, complete or partial. The term "substantially encapsulated" means that at least greater than 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, or greater than 99% of the pharmaceutical composition or compound of the present disclosure can be enclosed, surrounded or encased within the delivery agent. "Partial encapsulation" or “partially encapsulate” means that less than 10, 10, 20, 30, 4050 or less of the pharmaceutical composition or compound of the present disclosure can be enclosed, surrounded or encased within the delivery agent. Advantageously, encapsulation can be determined by measuring the escape or the activity of the pharmaceutical composition or compound of the present disclosure using fluorescence and / or electron micrograph. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, or greater than 99% of the pharmaceutical composition or compound of the present disclosure are encapsulated in the delivery agent. In some embodiments, the polynucleotides described herein can be encapsulated in a therapeutic nanoparticle, referred to herein as "therapeutic nanoparticle polynucleotides." Therapeutic nanoparticles can be formulated by methods described in, e.g., Intl. Pub. Nos. WO2010005740, WO2010030763, WO2010005721, WO2010005723, and WO2012054923; and U.S. Pub. Nos. US20110262491, US20100104645, US20100087337, US20100068285, US20110274759, US20100068286, US20120288541, US20120140790, US20130123351 and US20130230567; and U.S. Pat. Nos.8,206,747, 8,293,276, 8,318,208 and 8,318,211, each of which is herein incorporated by reference in its entirety. In some embodiments, the therapeutic nanoparticle polynucleotide can be formulated for sustained release. As used herein, "sustained release" refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. The period of time can include, but is not limited to, hours, days, weeks, months and years. As a non-limiting example, the sustained release nanoparticle of the polynucleotides described herein can be formulated as disclosed in Intl. Pub. PATENT ATTORNEY DOCKET NO.50858-153WO4 No. WO2010075072 and U.S. Pub. Nos. US20100216804, US20110217377, US20120201859 and US20130150295, each of which is herein incorporated by reference in their entirety. In some embodiments, the therapeutic nanoparticle polynucleotide can be formulated to be target specific, such as those described in Intl. Pub. Nos. WO2008121949, WO2010005726, WO2010005725, WO2011084521 and WO2011084518; and U.S. Pub. Nos. US20100069426, US20120004293 and US20100104655, each of which is herein incorporated by reference in its entirety. The LNPs can be prepared using microfluidic mixers or micromixers. Exemplary microfluidic mixers can include, but are not limited to, a slit interdigital micromixer including, but not limited to those manufactured by Microinnova (Allerheiligen bei Wildon, Austria) and / or a staggered herringbone micromixer (SHM) (see Zhigaltsevet al., "Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing," Langmuir 28:3633-40 (2012); Belliveau et al., "Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA," Molecular Therapy-Nucleic Acids.1:e37 (2012); Chen et al., "Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation," J. Am. Chem. Soc.134(16):6948-51 (2012); each of which is herein incorporated by reference in its entirety). Exemplary micromixers include Slit Interdigital Microstructured Mixer (SIMM-V2) or a Standard Slit Interdigital Micro Mixer (SSIMM) or Caterpillar (CPMM) or Impinging-jet (IJMM,) from the Institut für Mikrotechnik Mainz GmbH, Mainz Germany. In some embodiments, methods of making LNP using SHM further comprise mixing at least two input streams wherein mixing occurs by microstructure-induced chaotic advection (MICA). According to this method, fluid streams flow through channels present in a herringbone pattern causing rotational flow and folding the fluids around each other. This method can also comprise a surface for fluid mixing wherein the surface changes orientations during fluid cycling. Methods of generating LNPs using SHM include those disclosed in U.S. Pub. Nos. US20040262223 and US20120276209, each of which is incorporated herein by reference in their entirety. In some embodiments, the polynucleotides described herein can be formulated in lipid nanoparticles using microfluidic technology (see Whitesides, George M., "The Origins and the Future of Microfluidics," Nature 442: 368-373 (2006); and Abraham et al., "Chaotic Mixer for Microchannels," Science 295: 647-651 (2002); each of which is herein incorporated by reference in its entirety). In some embodiments, the polynucleotides can be formulated in lipid nanoparticles using a micromixer chip such as, but not limited to, those from Harvard Apparatus (Holliston, MA) or Dolomite Microfluidics (Royston, UK). A micromixer chip can be used for rapid mixing of two or more fluid streams with a split and recombine mechanism. In some embodiments, the polynucleotides described herein can be formulated in lipid nanoparticles having a diameter from about 1 nm to about 100 nm such as, but not limited to, about 1 nm to about 20 nm, from about 1 nm to about 30 nm, from about 1 nm to about 40 nm, from about 1 nm to about 50 nm, from about 1 nm to about 60 nm, from about 1 nm to about 70 nm, from about 1 nm to about 80 nm, from about 1 nm to about 90 nm, from about 5 nm to about from 100 nm, from about 5 nm to about 10 nm, about 5 nm to about 20 nm, from about 5 nm to about 30 nm, from about 5 nm to about 40 nm, from about 5 nm to about 50 nm, from about 5 nm to about 60 nm, from about 5 nm to about 70 nm, from about 5 nm to about 80 nm, from about 5 nm to about 90 nm, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 PATENT ATTORNEY DOCKET NO.50858-153WO4 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm, about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and / or about 90 to about 100 nm. In some embodiments, the lipid nanoparticles can have a diameter from about 10 to 500 nm. In some embodiments, the lipid nanoparticle can have a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm. In some embodiments, the polynucleotides can be delivered using smaller LNPs. Such particles can comprise a diameter from below 0.1 µm up to 100 nm such as, but not limited to, less than 0.1 µm, less than 1.0 µm, less than 5µm, less than 10 µm, less than 15 um, less than 20 um, less than 25 um, less than 30 um, less than 35 um, less than 40 um, less than 50 um, less than 55 um, less than 60 um, less than 65 um, less than 70 um, less than 75 um, less than 80 um, less than 85 um, less than 90 um, less than 95 um, less than 100 um, less than 125 um, less than 150 um, less than 175 um, less than 200 um, less than 225 um, less than 250 um, less than 275 um, less than 300 um, less than 325 um, less than 350 um, less than 375 um, less than 400 um, less than 425 um, less than 450 um, less than 475 um, less than 500 um, less than 525 um, less than 550 um, less than 575 um, less than 600 um, less than 625 um, less than 650 um, less than 675 um, less than 700 um, less than 725 um, less than 750 um, less than 775 um, less than 800 um, less than 825 um, less than 850 um, less than 875 um, less than 900 um, less than 925 um, less than 950 um, or less than 975 um. The nanoparticles and microparticles described herein can be geometrically engineered to modulate macrophage and / or the immune response. The geometrically engineered particles can have varied shapes, sizes and / or surface charges to incorporate the polynucleotides described herein for targeted delivery such as, but not limited to, pulmonary delivery (see, e.g., Intl. Pub. No. WO2013082111, herein incorporated by reference in its entirety). Other physical features the geometrically engineering particles can include, but are not limited to, fenestrations, angled arms, asymmetry and surface roughness, charge that can alter the interactions with cells and tissues. In some embodiment, the nanoparticles described herein are stealth nanoparticles or target- specific stealth nanoparticles such as, but not limited to, those described in U.S. Pub. No. US20130172406, herein incorporated by reference in its entirety. The stealth or target-specific stealth nanoparticles can comprise a polymeric matrix, which can comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), PATENT ATTORNEY DOCKET NO.50858-153WO4 polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polyesters, polyanhydrides, polyethers, polyurethanes, polymethacrylates, polyacrylates, polycyanoacrylates, or combinations thereof. 5. Therapeutic and Prophylactic Polypeptides The polynucleotides (e.g., synRNA molecules) described herein may encode a therapeutic or prophylactic polypeptide, such as a polypeptide that, when provided to a subject (e.g., a mammalian subject, such as a human), exerts a beneficial effect, such as the alleviation of one or more symptoms of a disease, diminishment of extent of a disease, stabilized (i.e., not worsening) state of a disease, delay or slowing of progression of a disease, amelioration or palliation of a state of a disease, or prevention of a disease state. The disease may be one that is associated with a deficiency in an endogenous version of the polypeptide. Alternatively, the disease may be one in which the polypeptide is naturally expressed as an antigen that is associated with the disease state. In some embodiments, the polypeptide encoded by the open reading frame is a secreted protein, (e.g., a cytokine, a growth factor, an enzyme, an immunomodulator, an antibody or antigen-binding fragment thereof, or a cell-penetrating peptide), an extracellular membrane-bound protein, an intracellular membrane-bound protein, a cytoplasmic protein, a cytoskeletal protein, or a nuclear protein. In some embodiments, the polypeptide is a protein of the human proteome. 6. Signal Sequences The polynucleotides (e.g., a RNA, e.g., an mRNA) of the present disclosure can also comprise nucleotide sequences that encode additional features that facilitate trafficking of the encoded polypeptides to therapeutically relevant sites. One such feature that aids in protein trafficking is the signal sequence or targeting sequence. The peptides encoded by these signal sequences are known by a variety of names, including targeting peptides, transit peptides, and signal peptides. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) comprises a nucleotide sequence (e.g., an ORF) that encodes a signal peptide operably linked to a nucleotide sequence that encodes a polypeptide of interest. In some embodiments, the "signal sequence" or "signal peptide" is a polynucleotide or polypeptide, respectively, which is from about 30-210, e.g., about 45-80 or 15-60 nucleotides (e.g., about 20, 30, 40, 50, 60, or 70 amino acids) in length that, optionally, is incorporated at the 5′ (or N-terminus) of the coding region or the polypeptide, respectively. Addition of these sequences results in trafficking the encoded polypeptide to a desired site, such as the endoplasmic reticulum or the mitochondria through one or more targeting pathways. Some signal peptides are cleaved from the protein, for example by a signal peptidase after the proteins are transported to the desired site. 7. Sequence Optimization of Nucleotide Sequences Encoding a Target Polypeptide In some embodiments, a polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure is sequence optimized. In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a nucleotide sequence (e.g., an ORF) encoding a therapeutic polypeptide PATENT ATTORNEY DOCKET NO.50858-153WO4 (e.g., a therapeutic polypeptide described above), optionally, a nucleotide sequence (e.g, an ORF) encoding another polypeptide of interest, a 5′-UTR, a 3′-UTR, the 5′ UTR or 3′ UTR optionally comprising at least one microRNA binding site, optionally a nucleotide sequence encoding a linker, a poly-A tail, or any combination thereof), in which the ORF(s) are sequence optimized. A sequence-optimized nucleotide sequence, e.g., a codon-optimized RNA sequence encoding a therapeutic polypeptide, is a sequence comprising at least one synonymous nucleobase substitution with respect to a reference sequence (e.g., a wild type nucleotide sequence encoding the therapeutic polypeptide of interest). A sequence-optimized nucleotide sequence can be partially or completely different in sequence from the reference sequence. For example, a reference sequence encoding polyserine uniformly encoded by UCU codons can be sequence-optimized by having 100% of its nucleobases substituted (for each codon, U in position 1 replaced by A, C in position 2 replaced by G, and U in position 3 replaced by C) to yield a sequence encoding polyserine which would be uniformly encoded by AGC codons. The percentage of sequence identity obtained from a global pairwise alignment between the reference polyserine nucleic acid sequence and the sequence-optimized polyserine nucleic acid sequence would be 0%. However, the protein products from both sequences would be 100% identical. Some sequence optimization (also sometimes referred to codon optimization) methods are known in the art (and discussed in more detail below) and can be useful to achieve one or more desired results. These results can include, e.g., matching codon frequencies in certain tissue targets and / or host organisms to ensure proper folding; biasing G / C content to increase mRNA stability or reduce secondary structures; minimizing tandem repeat codons or base runs that can impair gene construction or expression; customizing transcriptional and translational control regions; inserting or removing protein trafficking sequences; removing / adding post translation modification sites in an encoded protein (e.g., glycosylation sites); adding, removing or shuffling protein domains; inserting or deleting restriction sites; modifying ribosome binding sites and mRNA degradation sites; adjusting translational rates to allow the various domains of the protein to fold properly; and / or reducing or eliminating problem secondary structures within the polynucleotide. Sequence optimization tools, algorithms and services are known in the art, non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park CA) and / or proprietary methods. Codon options for each amino acid are given in Table 4. Table 4. Codon Options PATENT ATTORNEY DOCKET NO.50858-153WO4 In some embodiments, a polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a sequence-optimized nucleotide sequence (e.g., an ORF) encoding a therapeutic polypeptide, a functional fragment, or a variant thereof, wherein the therapeutic polypeptide, functional fragment, or a variant thereof encoded by the sequence-optimized nucleotide sequence has improved properties (e.g., compared to a therapeutic polypeptide, functional fragment, or a variant thereof encoded by a reference nucleotide sequence that is not sequence optimized), e.g., improved properties related to expression efficacy after administration in vivo. Such properties include, but are not limited to, improving nucleic acid stability (e.g., mRNA stability), increasing translation efficacy in the target tissue, reducing the number of truncated proteins expressed, improving the folding or prevent misfolding of the expressed proteins, reducing toxicity of the expressed products, reducing cell death caused by the expressed products, increasing and / or decreasing protein aggregation. In some embodiments, the sequence-optimized nucleotide sequence (e.g., an ORF) is codon optimized for expression in human subjects, having structural and / or chemical features that avoid one or more of the problems in the art, for example, features which are useful for optimizing formulation and delivery of nucleic acid-based therapeutics while retaining structural and functional integrity; overcoming a threshold of expression; improving expression rates; half-life and / or protein concentrations; optimizing protein localization; and avoiding deleterious bio-responses such as the immune response and / or degradation pathways. In some embodiments, the polynucleotides of the present disclosure comprise a nucleotide sequence (e.g., a nucleotide sequence (e.g., an ORF) encoding a therapeutic polypeptide, a nucleotide sequence (e.g., an ORF) encoding another polypeptide of interest, a 5′-UTR, a 3′-UTR, a microRNA binding site, a nucleic acid sequence encoding a linker, or any combination thereof) that is sequence- optimized according to a method comprising: PATENT ATTORNEY DOCKET NO.50858-153WO4 (i) substituting at least one codon in a reference nucleotide sequence (e.g., an ORF encoding a therapeutic polypeptide) with an alternative codon to increase or decrease uridine content to generate a uridine-modified sequence; (ii) substituting at least one codon in a reference nucleotide sequence (e.g., an ORF encoding a therapeutic polypeptide) with an alternative codon having a higher codon frequency in the synonymous codon set; (iii) substituting at least one codon in a reference nucleotide sequence (e.g., an ORF encoding a therapeutic polypeptide) with an alternative codon to increase G / C content; or (iv) a combination thereof. In some embodiments, the sequence-optimized nucleotide sequence (e.g., an ORF encoding a therapeutic polypeptide) has at least one improved property with respect to the reference nucleotide sequence. In some embodiments, the sequence optimization method is multiparametric and comprises one, two, three, four, or more methods disclosed herein and / or other optimization methods known in the art. Features, which can be considered beneficial in some embodiments of the present disclosure, can be encoded by or within regions of the polynucleotide and such regions can be upstream (5′) to, downstream (3′) to, or within the region that encodes the therapeutic polypeptide. These regions can be incorporated into the polynucleotide before and / or after sequence-optimization of the protein encoding region or open reading frame (ORF). Examples of such features include, but are not limited to, untranslated regions (UTRs), microRNA sequences, Kozak sequences, oligo(dT) sequences, poly-A tail, and detectable tags and can include multiple cloning sites that can have XbaI recognition. In some embodiments, the polynucleotide of the present disclosure comprises a 5′ UTR, a 3′ UTR and / or a microRNA binding site. In some embodiments, the polynucleotide comprises two or more 5′ UTRs and / or 3′ UTRs, which can be the same or different sequences. In some embodiments, the polynucleotide comprises two or more microRNA binding sites, which can be the same or different sequences. Any portion of the 5′ UTR, 3′ UTR, and / or microRNA binding site, including none, can be sequence-optimized and can independently contain one or more different structural or chemical modifications, before and / or after sequence optimization. In some embodiments, after optimization, the polynucleotide is reconstituted and transformed into a vector such as, but not limited to, plasmids, viruses, cosmids, and artificial chromosomes. For example, the optimized polynucleotide can be reconstituted and transformed into chemically competent E. coli, yeast, neurospora, maize, drosophila, etc. where high copy plasmid-like or chromosome structures occur by methods described herein. 8. Sequence-Optimized Nucleotide Sequences Encoding Target Polypeptides In some embodiments, the polynucleotide of the present disclosure comprises a sequence- optimized nucleotide sequence encoding a therapeutic polypeptide disclosed herein. In some embodiments, the polynucleotide of the present disclosure comprises an open reading frame (ORF) encoding a therapeutic polypeptide, wherein the ORF has been sequence optimized. PATENT ATTORNEY DOCKET NO.50858-153WO4 The sequence-optimized nucleotide sequences disclosed herein may be distinct from the corresponding wild type nucleotide acid sequences and from other known sequence-optimized nucleotide sequences, e.g., these sequence-optimized nucleic acids have unique compositional characteristics. In some embodiments, the percentage of uracil or thymine nucleobases in a sequence-optimized nucleotide sequence (e.g., encoding a therapeutic polypeptide, a functional fragment, or a variant thereof) is modified (e.g., reduced) with respect to the percentage of uracil or thymine nucleobases in the reference wild-type nucleotide sequence. Such a sequence is referred to as a uracil-modified or thymine- modified sequence. The percentage of uracil or thymine content in a nucleotide sequence can be determined by dividing the number of uracils or thymines in a sequence by the total number of nucleotides and multiplying by 100. In some embodiments, the sequence-optimized nucleotide sequence has a lower uracil or thymine content than the uracil or thymine content in the reference wild-type sequence. In some embodiments, the uracil or thymine content in a sequence-optimized nucleotide sequence of the present disclosure is greater than the uracil or thymine content in the reference wild-type sequence and still maintain beneficial effects, e.g., increased expression and / or reduced Toll-Like Receptor (TLR) response when compared to the reference wild-type sequence. Methods for optimizing codon usage are known in the art. For example, an ORF of any one or more of the sequences provided herein may be codon optimized. Codon optimization, in some embodiments, may be used to match codon frequencies in target and host organisms to ensure proper folding; bias GC content to increase mRNA stability or reduce secondary structures; minimize tandem repeat codons or base runs that may impair gene construction or expression; customize transcriptional and translational control regions; insert or remove protein trafficking sequences; remove / add post translation modification sites in encoded protein (e.g., glycosylation sites); add, remove or shuffle protein domains; insert or delete restriction sites; modify ribosome binding sites and mRNA degradation sites; adjust translational rates to allow the various domains of the protein to fold properly; or reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art - non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park CA) and / or proprietary methods. In some embodiments, the open reading frame (ORF) sequence is optimized using optimization algorithms. 9. Characterization of Sequence-Optimized Nucleic Acids In some embodiments of the present disclosure, the polynucleotide (e.g., a RNA, e.g., an mRNA) comprising a sequence optimized nucleic acid disclosed herein encoding a therapeutic polypeptide can be tested to determine whether at least one nucleic acid sequence property (e.g., stability when exposed to nucleases) or expression property has been improved with respect to the non-sequence optimized nucleic acid. As used herein, "expression property" refers to a property of a nucleic acid sequence either in vivo (e.g., translation efficacy of a synthetic mRNA after administration to a subject in need thereof) or in vitro (e.g., translation efficacy of a synthetic mRNA tested in an in vitro model system). Expression properties include but are not limited to the amount of protein produced by an mRNA encoding a therapeutic polypeptide after administration, and the amount of soluble or otherwise functional protein produced. In some embodiments, sequence optimized nucleic acids disclosed herein can be evaluated PATENT ATTORNEY DOCKET NO.50858-153WO4 according to the viability of the cells expressing a protein encoded by a sequence optimized nucleic acid sequence (e.g., a RNA, e.g., an mRNA) encoding a therapeutic polypeptide disclosed herein. In a given embodiment, a plurality of sequence optimized nucleic acids disclosed herein (e.g., a RNA, e.g., an mRNA) containing codon substitutions with respect to the non-optimized reference nucleic acid sequence can be characterized functionally to measure a property of interest, for example an expression property in an in vitro model system, or in vivo in a target tissue or cell. a. Optimization of Nucleic Acid Sequence Intrinsic Properties In some embodiments of the present disclosure, the desired property of the polynucleotide is an intrinsic property of the nucleic acid sequence. For example, the nucleotide sequence (e.g., a RNA, e.g., an mRNA) can be sequence optimized for in vivo or in vitro stability. In some embodiments, the nucleotide sequence can be sequence optimized for expression in a given target tissue or cell. In some embodiments, the nucleic acid sequence is sequence optimized to increase its plasma half-life by preventing its degradation by endo and exonucleases. In other embodiments, the nucleic acid sequence is sequence optimized to increase its resistance to hydrolysis in solution, for example, to lengthen the time that the sequence optimized nucleic acid or a pharmaceutical composition comprising the sequence optimized nucleic acid can be stored under aqueous conditions with minimal degradation. In other embodiments, the sequence optimized nucleic acid can be optimized to increase its resistance to hydrolysis in dry storage conditions, for example, to lengthen the time that the sequence optimized nucleic acid can be stored after lyophilization with minimal degradation. b. Nucleic Acids Sequence Optimized for Protein Expression In some embodiments of the present disclosure, the desired property of the polynucleotide is the level of expression of a therapeutic polypeptide encoded by a sequence optimized sequence disclosed herein. Protein expression levels can be measured using one or more expression systems. In some embodiments, expression can be measured in cell culture systems, e.g., CHO cells or HEK293 cells. In some embodiments, expression can be measured using in vitro expression systems prepared from extracts of living cells, e.g., rabbit reticulocyte lysates, or in vitro expression systems prepared by assembly of purified individual components. In other embodiments, the protein expression is measured in an in vivo system, e.g., mouse, rabbit, monkey, etc. In some embodiments, protein expression in solution form can be desirable. Accordingly, in some embodiments, a reference sequence can be sequence optimized to yield a sequence optimized nucleic acid sequence having optimized levels of expressed proteins in soluble form. Levels of protein expression and other properties such as solubility, levels of aggregation, and the presence of truncation products (i.e., fragments due to proteolysis, hydrolysis, or defective translation) can be measured according to methods known in the art, for example, using electrophoresis (e.g., native or SDS-PAGE) or chromatographic methods (e.g., HPLC, size exclusion chromatography, etc.). PATENT ATTORNEY DOCKET NO.50858-153WO4 c. Optimization of Target Tissue or Target Cell Viability In some embodiments, the expression of heterologous therapeutic proteins encoded by a nucleic acid sequence can have deleterious effects in the target tissue or cell, reducing protein yield, or reducing the quality of the expressed product (e.g., due to the presence of protein fragments or precipitation of the expressed protein in inclusion bodies), or causing toxicity. Accordingly, in some embodiments of the present disclosure, the sequence optimization of a nucleic acid sequence disclosed herein, e.g., a nucleic acid sequence encoding a therapeutic polypeptide, can be used to increase the viability of target cells expressing the protein encoded by the sequence optimized nucleic acid. Heterologous protein expression can also be deleterious to cells transfected with a nucleic acid sequence for autologous or heterologous transplantation. Accordingly, in some embodiments of the present disclosure the sequence optimization of a nucleic acid sequence disclosed herein can be used to increase the viability of target cells expressing the protein encoded by the sequence optimized nucleic acid sequence. Changes in cell or tissue viability, toxicity, and other physiological reactions can be measured according to methods known in the art. 10. Modified Nucleotide Sequences Encoding Target Polypeptides In some embodiments, the polynucleotide (e.g., a RNA, e.g., an mRNA) of the present disclosure comprises a chemically modified nucleobase, for example, a chemically modified uracil, e.g., pseudouracil, N1-methylpseudouracil, 5-methoxyuracil, or the like. In some embodiments, the mRNA is a uracil-modified sequence comprising an ORF encoding a therapeutic polypeptide, wherein the mRNA comprises a chemically modified nucleobase, for example, a chemically modified uracil, e.g., pseudouracil, N1-methylpseudouracil, or 5-methoxyuracil. In certain aspects of the present disclosure, when the modified uracil base is connected to a ribose sugar, as it is in polynucleotides, the resulting modified nucleoside or nucleotide is referred to as modified uridine. In some embodiments, uracil in the polynucleotide is at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least 90%, at least 95%, at least 99%, or about 100% modified uracil. In some embodiments, uracil in the polynucleotide is at least 95% modified uracil. In some embodiments, uracil in the polynucleotide is 100% modified uracil. In embodiments where uracil in the polynucleotide is at least 95% modified uracil overall uracil content can be adjusted such that an mRNA provides suitable protein expression levels while inducing little to no immune response. In some embodiments, the uracil content of the ORF is between about 100% and about 150%, between about 100% and about 110%, between about 105% and about 115%, between about 110% and about 120%, between about 115% and about 125%, between about 120% and about 130%, between about 125% and about 135%, between about 130% and about 140%, between about 135% and about 145%, between about 140% and about 150% of the theoretical minimum uracil content in the corresponding wild-type ORF (%UTM). In other embodiments, the uracil content of the ORF is between about 121% and about 136% or between 123% and 134% of the %UTM. In some embodiments, the uracil content of the ORF encoding a therapeutic polypeptide is about 115%, about PATENT ATTORNEY DOCKET NO.50858-153WO4 120%, about 125%, about 130%, about 135%, about 140%, about 145%, or about 150% of the %UTM. In this context, the term "uracil" can refer to modified uracil and / or naturally occurring uracil. In some embodiments, the uracil content in the ORF of the mRNA encoding a therapeutic polypeptide of the present disclosure is less than about 30%, about 25%, about 20%, about 15%, or about 10% of the total nucleobase content in the ORF. In some embodiments, the uracil content in the ORF is between about 10% and about 20% of the total nucleobase content in the ORF. In other embodiments, the uracil content in the ORF is between about 10% and about 25% of the total nucleobase content in the ORF. In some embodiments, the uracil content in the ORF of the mRNA encoding a therapeutic polypeptide is less than about 20% of the total nucleobase content in the open reading frame. In this context, the term "uracil" can refer to modified uracil and / or naturally occurring uracil. In further embodiments, the ORF of the mRNA encoding a therapeutic polypeptide having modified uracil and adjusted uracil content has increased Cytosine (C), Guanine (G), or Guanine / Cytosine (G / C) content (absolute or relative). In some embodiments, the overall increase in C, G, or G / C content (absolute or relative) of the ORF is at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 100% relative to the G / C content (absolute or relative) of the wild-type ORF. In some embodiments, the G, the C, or the G / C content in the ORF is less than about 100%, less than about 90%, less than about 85%, or less than about 80% of the theoretical maximum G, C, or G / C content of the corresponding wild type nucleotide sequence encoding the therapeutic polypeptide (%GTMX; %CTMX, or %G / CTMX). In some embodiments, the increases in G and / or C content (absolute or relative) described herein can be conducted by replacing synonymous codons with low G, C, or G / C content with synonymous codons having higher G, C, or G / C content. In other embodiments, the increase in G and / or C content (absolute or relative) is conducted by replacing a codon ending with U with a synonymous codon ending with G or C. In further embodiments, the ORF of the mRNA encoding a therapeutic polypeptide of the present disclosure comprises modified uracil and has an adjusted uracil content containing less uracil pairs (UU) and / or uracil triplets (UUU) and / or uracil quadruplets (UUUU) than the corresponding wild-type nucleotide sequence encoding the therapeutic polypeptide. In some embodiments, the ORF of the mRNA encoding a therapeutic polypeptide of the present disclosure contains no uracil pairs and / or uracil triplets and / or uracil quadruplets. In some embodiments, uracil pairs and / or uracil triplets and / or uracil quadruplets are reduced below a certain threshold, e.g., no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 occurrences in the ORF of the mRNA encoding the therapeutic polypeptide. In a particular embodiment, the ORF of the mRNA encoding the therapeutic polypeptide of the present disclosure contains less than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non- phenylalanine uracil pairs and / or triplets. In some embodiments, the ORF of the mRNA encoding the therapeutic polypeptide contains no non-phenylalanine uracil pairs and / or triplets. In further embodiments, the ORF of the mRNA encoding a therapeutic polypeptide of the present disclosure comprises modified uracil and has an adjusted uracil content containing less uracil-rich clusters than the corresponding wild-type nucleotide sequence encoding the therapeutic polypeptide. In some embodiments, the ORF of the mRNA encoding the therapeutic polypeptide of the present PATENT ATTORNEY DOCKET NO.50858-153WO4 disclosure contains uracil-rich clusters that are shorter in length than corresponding uracil-rich clusters in the corresponding wild-type nucleotide sequence encoding the therapeutic polypeptide. In further embodiments, alternative lower frequency codons are employed. At least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% of the codons in the therapeutic polypeptide–encoding ORF of the modified uracil-comprising mRNA are substituted with alternative codons, each alternative codon having a codon frequency lower than the codon frequency of the substituted codon in the synonymous codon set. The ORF also has adjusted uracil content, as described above. In some embodiments, at least one codon in the ORF of the mRNA encoding the therapeutic polypeptide is substituted with an alternative codon having a codon frequency lower than the codon frequency of the substituted codon in...

Claims

PATENT ATTORNEY DOCKET NO.50858-153WO4 CLAIMS 1. A synthetic RNA molecule (synRNA) comprising, in the 5’-to-3’ direction: a) a 5’ cap structure; b) a 5’ untranslated region (UTR); c) an open reading frame (ORF) encoding a polypeptide; d) a 3’ UTR; and e) a poly-A region; wherein a) each of the 5’UTR, the 3’UTR, and the poly-A region comprises at least one 2’ modified nucleoside, and / or b) the ORF comprises at least one codon of Formula SYN-I: -L1-B1-L2-B2-L3-B3-L4- (SYN-I) wherein: each of L1, L2, L3, and L4is, independently, an unmodified internucleoside linkage or a modified internucleoside linkage; each of B1, B2, and B3is, independently, an unmodified nucleoside or a 2’ modified nucleoside; and (i) at least one of L1, L2, L3, and L4is a modified internucleoside linkage or (ii) at least one of B1, B2, and B3is a 2’ modified nucleoside; further wherein: when B1is a 2’ modified nucleoside, (i) at least one of B2and B3is a modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B2is a 2’ modified nucleoside, (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; when B3is a 2’ modified nucleoside, (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside; and when one or more of L1, L2, L3, and L4is a modified internucleoside linkage, (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, or (iv) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside.

2. The synRNA of claim 1, wherein B1is a 2’ modified nucleoside, and (i) at least one of B2and B3is a 2’ modified nucleoside or (ii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside.

3. The synRNA of claim 1 or 2, wherein B2is a 2’ modified nucleoside, and (i) at least one of B1and B3is a 2’ modified nucleoside, (ii) B2is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside.PATENT ATTORNEY DOCKET NO.50858-153WO4 4. The synRNA of any one of claims 1-3, wherein B3is a 2’ modified nucleoside, and (i) at least one of B1and B2is a 2’ modified nucleoside, (ii) B3is the only 2’ modified nucleoside in the codon, or (iii) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside.

5. The synRNA of any one of claims 1-4, wherein at least one of L1, L2, L3, or L4is a modified internucleoside linkage, and (i) at least another of L1, L2, L3, and L4is a modified internucleoside linkage, (ii) B1is an unmodified nucleoside and B2or B3is a 2’ modified nucleoside, (iii) each of B1, B2, and B3is a 2’ modified nucleoside, or (iv) the 5’ UTR, 3’ UTR, or poly-A region comprises a 2’ modified nucleoside.

6. The synRNA of any one of claims 1-5, wherein the synRNA comprises a 2’ modified nucleoside in the 5’ UTR.

7. The synRNA of claim 6, wherein each nucleoside in the 5’ UTR is a 2’ modified nucleoside.

8. The synRNA of any one of claims 1-7, wherein the synRNA comprises a 2’ modified nucleoside in the 3’ UTR.

9. The synRNA of claim 8, wherein each nucleoside in the 3’ UTR is a 2’ modified nucleoside.

10. The synRNA of any one of claims 1-9, wherein the synRNA comprises a 2’ modified nucleoside in the poly-A region.

11. The synRNA of claim 10, wherein each nucleoside in the poly-A region is a 2’ modified nucleoside.

12. The synRNA of any one of claims 6-11, wherein the 2’ modified nucleoside is a 2’-methoxy nucleoside.

13. The synRNA of claim 12, wherein each nucleoside in the 3’ UTR, the 5’ UTR, and the poly-A region is a 2’-methoxy nucleoside.

14. The synRNA of any one of claims 1-13, wherein each modified internucleoside linkage is, independently, selected from the group consisting of a phosphorothioate, a phosphoroselenate, a boranophosphate, a boranophosphate ester, a hydrogen phosphonate, a phosphoramidate, a phosphorodiamidate, an alkyl phosphonate, an aryl phosphonate, a phosphotriester, a phosphorodithioate, a bridged phosphoramidate, a bridged phosphorothioate, a bridged methylene- phosphonate, and an α-thio phosphate, optionally wherein each modified internucleoside linkage is a phosphorothioate internucleoside linkage.PATENT ATTORNEY DOCKET NO.50858-153WO4 15. The synRNA of any one of claims 1-14, wherein the each 2’ ribose modification is, independently, a 2’-O-methyl ribose or a 2’-fluoro ribose.

16. The synRNA of any one of claims 1-15, wherein the poly-A region is bound, at its 3’ end, to a modified nucleoside.

17. The synRNA of claim 16, wherein the modified nucleoside bound to the poly-A region is an inverted deoxythymidine.

18. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-III: -L1-F-L2-B2-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B2and B3is an unmodified nucleoside.

19. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-IV: -L1-B1-L2-B2-L3-F-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside.

20. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-VII: -S-B1-L2-B2-L3- B3-S- wherein: S is a phosphorothioate internucleoside linkage; each of L2and L3is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside.

21. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-XII: -L1-B1-L2-F-L3-B3-L4- wherein: F is a 2’-fluoro nucleoside; each of L1, L2, L3, and L4is an unmodified internucleoside linkage; and each of B1and B3is an unmodified nucleoside.PATENT ATTORNEY DOCKET NO.50858-153WO4 22. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-XVIII: -L1-B1-S-B2-L3- B3-L4- wherein: S is a phosphorothioate internucleoside linkage each of L1, L3and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside.

23. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-XIX: -L1-B1-L2-B2-S- B3-L4- wherein: S is a phosphorothioate internucleoside linkage; each of L1, L2and L4is an unmodified internucleoside linkage; and each of B1and B2is an unmodified nucleoside.

24. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-XXIV: -L1-B1-L2-B2-L3-B3-Z- wherein: each of L1, L2, and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure:.

25. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-XXV: -L1-B1-Z-B2-L3-B3-L4- wherein: each of L1, L3, and L4is a phosphodiester internucleoside linkage; and each of B1, B2, and B3is an unmodified nucleoside; and Z represents a modified internucleoside linkage of the following structure:.PATENT ATTORNEY DOCKET NO.50858-153WO4 26. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN-XXXV: -L1-F-L2-B2-S-B3-L4- wherein: each of L1, L2, and L4are phosphorothioate internucleoside linkages; each of B2and B3is an unmodified nucleoside; and F is a 2’-fluoro nucleoside.

27. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN- XLII: -L1-N-L2-B2-L3-B3-L4- wherein: each of L1, L2L3, and L4is a phosphodiester internucleoside linkage; each of B2and B3is an unmodified nucleoside; and N is a 2’-NH2 nucleoside.

28. The synRNA of any one of claims 1-17, wherein the codon has the structure of Formula SYN- XLV: -L1-B1-L2-B2-Q-B3-L4- wherein: each of L1, L2and L3is a phosphodiester internucleoside linkage; each of B1, B2, and B3is an unmodified nucleoside; and Q represents a modified internucleoside linkage of the following structure:.

29. The synRNA of any one of claims 1-28, wherein exactly one codon in the ORF has the structure of Formula SYN-I.

30. The synRNA of any one of claims 1-28, wherein a plurality of codons in the ORF has the structure of Formula SYN-I.

31. The synRNA of claim 30, wherein all codons in the ORF have the structure of Formula SYN- I.

32. The synRNA of claim 1, wherein the ORF does not comprise a 2’-modification or a modified internucleoside linkage.

33. The synRNA of claim 32, wherein the synRNA comprises, in the 5’-to-3’ direction: a) a 5’ cap structure;PATENT ATTORNEY DOCKET NO.50858-153WO4 b) a 5’ UTR consisting of 2’-methoxy nucleosides; c) an ORF encoding a polypeptide that does not comprise a 2’-modification or a modified internucleoside linkage; d) a 3’ UTR consisting of 2’-methoxy nucleosides; and e) a poly-A region consisting of 2’-methoxy nucleosides.

34. The synRNA of claim 1, wherein the synRNA comprises, in the 5’-to-3’ direction: a) a 5’ cap structure; b) a 5’ UTR consisting of 2’-methoxy nucleosides; c) an ORF encoding a polypeptide, wherein all codons in the ORF have the structure of Formula SYN-III or SYN-XXXV; d) a 3’ UTR consisting of 2’-methoxy nucleosides; and e) a poly-A region consisting of 2’-methoxy nucleosides.

35. The synRNA of any one of claims 1-34, wherein one or more of the nucleosides in the ORF comprises a nucleobase modification.

36. The synRNA of any one of claims 1-35, wherein one or more of the 2’ modified nucleosides in the ORF further comprises a nucleobase modification.

37. The synRNA of claim 35 or 36, wherein the nucleobase modification is N1-methyl- pseudouracil.

38. The synRNA of claim 37, wherein each uracil nucleobase in the ORF comprises the N1- methyl-pseudouracil nucleobase modification.

39. A method of increasing the stability or expression of a polypeptide-encoding RNA, the method comprising designing an ORF encoding the polypeptide and incorporating the ORF into the synRNA of any one of claims 1-38.

40. A method of expressing a polypeptide of interest in a subject, the method comprising administering to the subject the synRNA of any one of claims 1-38, wherein the ORF encodes the polypeptide of interest.

41. A host cell comprising the synRNA of any one of claims 1-38.

42. A kit comprising (i) the synRNA of any one of claims 1-38, and (ii) a package insert, wherein the package insert instructs a user of the kit to perform the method of claim 39 or 40.

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