Compositions comprising circular polyribonucleotides and uses thereof

Abstract

The disclosure provides compositions, pharmaceutical preparations, and uses of circular polyribonucleotides complexed with one or more targeting moieties. The disclosure further discloses methods of using targeting moieties complexed with a circular polyribonucleotide to achieve functional delivery of a polypeptide to a cell.

Description

COMPOSITIONS COMPRISING CIRCULAR POLYRIBONUCLEOTIDES AND USES THEREOFCross-Reference To Related ApplicationsThis application claims priority to Greek Provisional Application No. 20230100684, filed August 18, 2023, U.S. Provisional Application No. 63 / 533,529, filed August 18, 2023, and U.S. Provisional Application No. 63 / 551 ,834, filed February 9, 2024, each of which is incorporated by reference in entirety.Sequence ListingThis application contains a Sequence Listing which has been filed electronically in Extensible Markup Language (XML) format and is hereby incorporated by reference in its entirety. Said XML copy, created on August 16, 2024, is named 51509-052WO3_Sequence_Listing_8_16_24.XML and is 100,545 bytes in size.BackgroundThousands of circular polyribonucleotides are expressed from human genomes. Circular polyribonucleotides are produced endogenously by backsplicing, a process in which the spliceosome fuses a splice donor site in a downstream exon to a splice acceptor site in an upstream exon. Circular polyribonucleotides are produced in cells with high cell-type specificity and can exert biologically meaningful and specific functions. Circular polyribonucleotides are being developed for use in modulating biological systems, including in therapeutic applications. There remains a need to develop improved compositions and methods for the delivery of circular polyribonucleotides in vivo.SummaryThis disclosure provides compositions, pharmaceutical preparations, and uses of circular polyribonucleotides complexed with one or more targeting moieties.In an aspect, the disclosure provides a complex including A and Xn(L-B)z, wherein A is a circular polyribonucleotide, each X is independently a moiety that binds specifically to a region of A, each L is independently a linker, each B is independently a targeting moiety, wherein n is an integer from 1 to 20 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), and wherein z is an integer from 1 to 5 (1 , 2, 3, 4, or 5). In some embodiments, n is an integer from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20). In some embodiments, n is an integer from 1 to 5 (e.g., 1 , 2, 3, 4, or 5). In some embodiments, z is an integer from 1 to 3 (e.g., 1 , 2, or 3). In some embodiments, z is 1 . In some embodiments, z is 2. In some embodiments, Xn(L-B)zincludes Xn(L-B1)zand Xn(L-B2)z, where B1is a first targeting moiety and B2is a second targeting moiety. In some embodiments, Xn(L-B)zincludes Xn(L1-B)zand Xn(L2-B)z, where L1is a first linker and L2is a second linker. In some embodiments, Xn(L-B)zincludes Xi-(L-B)zand X2-(L-B)Z, where Xi is a first moiety that binds specifically to a first region of A and X2 is a second moiety that binds specifically to a second region of A. In some embodiments, Xn(L-B)zincludes B1-L- X-L- B2, where B1is a first targeting moiety and B2is a second targeting moiety. In some embodiments, Xn(L-B)zincludes B-L1-X-L2-B, where L1is a first linker and L2is a second linker.This disclosure also provides compositions, pharmaceutical preparations, and uses of circular polyribonucleotides complexed with one or more targeting moieties with one or more photoreactive crosslinking agents. In some embodiments, each X includes a photoreactive crosslinking agent.In an aspect, the disclosure provides a complex including A and Xn(L-B)z, wherein A is a circular polyribonucleotide, each X is independently a moiety that binds specifically to a region of A and includes a photoreactive crosslinking agent, each L is independently a linker, each B is independently a targeting moiety, wherein n is an integer from 1 to 20 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), and wherein z is an integer from 1 to 5 (1 , 2, 3, 4, or 5). In some embodiments, n is an integer from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20). In some embodiments, n is an integer from 1 to 5 (e.g., 1 , 2, 3, 4, or 5). In some embodiments, z is an integer from 1 to 3 (e.g., 1 , 2, or 3). In some embodiments, z is 1 . In some embodiments, z is 2. In some embodiments, Xn(L-B)zincludes Xn(L-B1)zand Xn(L-B2)z, where B1is a first targeting moiety and B2is a second targeting moiety. In some embodiments, Xn(L-B)zincludes Xn(L1-B)zand Xn(l_2-B)z, where L1is a first linker and L2is a second linker. In some embodiments, Xn(L-B)zincludes Xi-(L-B)zand X2-(L-B)Z, where Xi is a first moiety that binds specifically to a first region of A and X2 is a second moiety that binds specifically to a second region of A. In some embodiments, Xn(L-B)zincludes B1-L- X-L-B2, where B1is a first targeting moiety and B2is a second targeting moiety. In some embodiments, Xn(L-B)zincludes B-L1- X-L2-B, where L1is a first linker and L2is a second linker.In some embodiments, X is an oligonucleotide. In some embodiments, the oligonucleotide includes a ribonucleic acid, a deoxyribonucleic acid, a peptide nucleic acid, a locked nucleic acid, or a glycol nucleic acid. In some embodiments, the oligonucleotide includes a photoreactive crosslinking agent. In some embodiments, the photoreactive crosslinking agent is attached to the 5’ end of the oligonucleotide. In some embodiments, the photoreactive crosslinking reagent is attached to the 3’ end of the oligonucleotide. In some embodiments, the photoreactive crosslinking agent is a photoreactive nucleotide analog. In some embodiments, the photoreactive crosslinking agent is a photoreactive nucleotide analog, optionally wherein the photoreactive nucleotide analog replaces a single nucleotide within the oligonucleotide. In some embodiments, the photoreactive nucleotide analog is located at an internal position within the oligonucleotide. In some embodiments, the 3’ end of the oligonucleotide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the photoreactive nucleotide analog. In some embodiments, the 3’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) nucleotides from the photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) nucleotides from the photoreactive nucleotide analog. In some embodiments, the photoreactive nucleotide analog crosslinks to a complementary ribonucleotide or a ribonucleotide located 1 base upstream or 1 base downstream of the complementary ribonucleotide within the circular polyribonucleotide upon photoirradiation.In some embodiments, the photoreactive crosslinking agent includes 5-bromo-2’-deoxyuridine (BrdU), a carbazole, a psoralen, a coumarin, 4’-thiouridine, a diazirine, a phenylselenide, a furan, or an abasic site.In some embodiments, the carbazole is a vinylcarbazole, e.g., 3-cyanovinylcarbazole, 4- methylpyranocarbazole, or pyranocarbazole.In some embodiments, the coumarin is 7-hydroxycoumarin.In some embodiments, the oligonucleotide includes a plurality of photoreactive crosslinking agents. In some embodiments, each of the plurality of photoreactive crosslinking agents is a photoreactive nucleotide analog. In some embodiments, each photoreactive nucleotide analog replaces a single nucleotide within the oligonucleotide. In some embodiments, each photoreactive nucleotide analog is located at an internal position within the oligonucleotide. In some embodiments, the 3’ end of the oligonucleotide has at least 1 , at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nearest photoreactive nucleotide analog. In some embodiments, the 3’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) nucleotides from the nearest photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nearest photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) nucleotides from the nearest photoreactive nucleotide analog.In some embodiments, at least one of the photoreactive nucleotide analogs is attached to the 3’ end of the oligonucleotide. In some embodiments, at least one of the photoreactive nucleotide analogs is attached to the 5’ end of the oligonucleotide.In some embodiments, the oligonucleotide includes 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) nucleotides between each of the photoreactive nucleotide analogs. In some embodiments, each of the photoreactive nucleotide analogs crosslinks to a complementary ribonucleotide or a ribonucleotide located 1 base upstream or 1 base downstream of the complementary ribonucleotide within the circular polyribonucleotide upon photoirradiation. In some embodiments, the oligonucleotide includes an aptamer.In some embodiments, the circular polyribonucleotide is bound to from 1 to 100, 1 and 50, 1 and 20, or 1 and 10 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) oligonucleotides, wherein each oligonucleotide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 2 to 10, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 oligonucleotides wherein each oligonucleotide is complexed to at least one targeting moiety. In some embodiments, the oligonucleotide is from 5 to 100 (e.g., 5 to 80, 5 to 60, 5 to 40, 5 to 20, 20 to 100, 40 to 100, 60 to 100, 80 to 100, 20 to 60, or 10 to 50) nucleotides in length.In some embodiments, the circular polynucleotide includes a binding region that anneals to the oligonucleotide. In some embodiments, the circular polynucleotide includes one or more binding regions each including from 5 to 200, e.g., 6 to 200, e.g., 7 to 200, e.g., 8 to 200 (e.g., from 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 50, 8 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein each binding region binds to an oligonucleotide. In some embodiments, each binding region includes at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 100% complementarity to the oligonucleotide. In some embodiments, the binding region has zero or one mismatch with the oligonucleotide.In some embodiments, X is a polypeptide. In some embodiments, the polypeptide includes a photoreactive crosslinking agent. In some embodiments, the photoreactive crosslinking agent is a photoreactive amino acid analog. In some embodiments, the photoreactive crosslinking agent is a photoreactive amino acid analog, optionally wherein the photoreactive amino acid analog replaces a single amino acid within the polypeptide. In some embodiments, the photoreactive amino acid analog is located at an internal position within the polypeptide. In some embodiments, the N-terminus of the polypeptide has at least 1 , e.g., at least 2, 3, 4, 5, 6, 7, or 8 amino acids from the photoreactive amino acid analog. In some embodiments, the N-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids from the photoreactive amino acid analog. In some embodiments, the C-terminus of the polypeptide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, or 8 amino acids from the photoreactive amino acid analog. In some embodiments, the C-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids from the photoreactive amino acid analog. In some embodiments, the photoreactive amino acid analog is attached to the N-terminus of the polypeptide. In some embodiments, the photoreactive nucleotide analog is attached to the C-terminus of the polypeptide. In some embodiments, the photoreactive amino acid analog crosslinks to a complementary ribonucleotide within the circular polyribonucleotide upon photoirradiation. In some embodiments, the photoreactive amino acid analog is an alkyl diazirene-based, arylazide-based, benzophenone-based unnatural amino acid, or A / -e-[2-(furan-2-yl)ethoxy]carbonyl-lysine.In some embodiments, the polypeptide includes a plurality of photoreactive crosslinking agents. In some embodiments, each of the plurality of photoreactive crosslinking agents is a photoreactive amino acid analog. In some embodiments, each of the plurality of photoreactive crosslinking agents replaces a single amino acid within the polypeptide. In some embodiments, at least one photoreactive amino acid analog is located at an internal position within the polypeptide. In some embodiments, the N-terminus of the polypeptide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, or 8 amino acids from the nearest photoreactive amino acid analog. In some embodiments, the N-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids from the nearest photoreactive amino acid analog. In some embodiments, the C-terminus of the polypeptide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, or 8 amino acids from the nearest photoreactive amino acid analog. In some embodiments, the C-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids from the nearest photoreactive amino acid analog. In some embodiments, at least one of the photoreactive amino acid analogs is attached to the N-terminus of the polypeptide. In some embodiments, at least one of the photoreactive amino acid analogs is attached to the C-terminus of the polypeptide. In some embodiments, the polypeptide includes 1 to 50, e.g., 2 to 50, e.g., 8 to 50 (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids between each of the photoreactive amino acid analogs. In some embodiments, each of the photoreactive amino acids crosslinks to a complementary ribonucleotide within the circular polyribonucleotide upon photoirradiation. In some embodiments, each photoreactive aminoacid analog is an alkyl diazirene-based, arylazide-based, benzophenone-based unnatural amino acid, or A / -e-[2-(furan-2-yl)ethoxy]carbonyl-lysine.In some embodiments, the polypeptide includes an RNA recognition motif wherein the RNA recognition motif is selected from a K homology domain, a zinc finger motif, a Pumilio homology domain, pentatricopeptide repeat domain, pseudouridine synthase and archaeosine transglycosylase domain, a THUMP domain, a YT521 -B homology domain, a double stranded RNA binding domain, a helicase domain, a cold shock domain, an S1 domain, an Sm domain, a La motif, a Piwi-Argonaute-Zwille domain, or an intrinsically disordered region.In some embodiments, the circular polyribonucleotide is bound to from 1 to 100, 1 to 50, 1 to 20, or 1 to 10 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) polypeptides, wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 polypeptides wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide includes one or more protein binding regions each including from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein each protein binding region binds to a polypeptide.In another aspect, the disclosure provides a complex that includes A and Xn(L-B)z, wherein A is a circular polyribonucleotide, each X is independently a moiety that binds specifically and is covalently attached to a region of A, each L is independently a linker, each B is independently a targeting moiety, wherein n is an integer from 1 to 20 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20), and wherein z is an integer from 1 to 5 (1 , 2, 3, 4, or 5). In some embodiments, n is an integer from 2 to 20 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20). In some embodiments, n is an integer from 1 to 5 (e.g., 1 , 2, 3, 4, or 5). In some embodiments, z is an integer from 1 to 3 (e.g., 1 , 2, or 3). In some embodiments, z is 1 . In some embodiments, z is 2. In some embodiments, Xn(L-B)zincludes Xn(L-B1)zand Xn(L-B2)z, where B1is a first targeting moiety and B2is a second targeting moiety. In some embodiments, Xn(L-B)zincludes Xn(L1-B)zand Xn(L2-B)z, where L1is a first linker and L2is a second linker. In some embodiments, Xn(L-B)zincludes Xi-(L-B)zand X2-(L-B)Z, where Xi is a first moiety that binds specifically and covalently attaches to a first region of A and X2 is a second moiety that binds specifically and covalently attaches to a second region of A. In some embodiments, Xn(L-B)zincludes B1- L- X-L-B2, where B1is a first targeting moiety and B2is a second targeting moiety. In some embodiments, Xn(L-B)zincludes B-L1-X-L2-B, where L1is a first linker and L2is a second linker.In some embodiments, X is an oligonucleotide. In some embodiments, the oligonucleotide includes a ribonucleic acid, a deoxyribonucleic acid, a peptide nucleic acid, a locked nucleic acid, or a glycol nucleic acid. In some embodiments, the oligonucleotide includes an aptamer.In some embodiments, the circular polyribonucleotide is bound to from 1 to 100, 1 and 50, 1 and 20, or 1 and 10 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) oligonucleotides, wherein each oligonucleotide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 2 to 10, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 oligonucleotides wherein each oligonucleotide is complexed to at least one targeting moiety. In some embodiments, the oligonucleotide is from 5 to 100 (e.g., 5 to 80, 5 to 60, 5 to 40, 5 to 20, 20 to 100, 40 to 100, 60 to 100, 80 to 100, 20 to 60, or 10 to 50) nucleotides in length.In some embodiments, the circular polynucleotide includes a binding region that anneals to the oligonucleotide. In some embodiments, the circular polynucleotide includes one or more binding regions each including from 5 to 200, e.g., 6 to 200, e.g., 7 to 200, e.g., 8 to 200 (e.g., from 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 50, 8 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein each binding region binds to an oligonucleotide. In some embodiments, each binding region includes at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 100% complementarity to the oligonucleotide. In some embodiments, the binding region has zero or one mismatch with the oligonucleotide.In some embodiments, X is a polypeptide. In some embodiments, the polypeptide includes an RNA recognition motif wherein the RNA recognition motif is selected from a K homology domain, a zinc finger motif, a Pumilio homology domain, pentatricopeptide repeat domain, pseudouridine synthase and archaeosine transglycosylase domain, a THUMP domain, a YT521 -B homology domain, a double stranded RNA binding domain, a helicase domain, a cold shock domain, an S1 domain, an Sm domain, a La motif, a Piwi-Argonaute-Zwille domain, or an intrinsically disordered region.In some embodiments, the circular polyribonucleotide is bound to from 1 to 100, 1 to 50, 1 to 20, or 1 to 10 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) polypeptides, wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 polypeptides wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide includes one or more protein binding regions each including from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein each protein binding region binds to a polypeptide.In some embodiments, the targeting moiety includes a small molecule, a polypeptide, a carbohydrate, a lipid, a nucleic acid, or a combination thereof. In some embodiments, the targeting moiety includes a small molecule.In some embodiments, the small molecule is selected from folic acid, urea, a-mannose, high mannose, ursodeoxycholic acid, an endosomal escape agent, or lithocholic acid.In some embodiments, the targeting moiety includes a polypeptide. In some embodiments, the polypeptide is a cell-penetrating peptide. In some embodiments, the polypeptide is selected from ASSLNIA (SEQ ID NO: 19), M12, RGD, melittin, LPS-binding protein (LBP) peptide, an adipose-homing peptide, or an endolytic peptide. In some embodiments, the polypeptide is an antibody or a target-binding fragment thereof. In some embodiments, the antibody or target-binding fragment thereof is selected from a monoclonal antibody or target-binding fragment thereof, a single-chain Fv molecule (scFv), a diabody, a triabody, a nanobody, an antibody-like protein scaffold, a domain antibody, a Fv fragment, a Fab fragment, a F(ab’)2 molecule, or a tandem scFv (taFv). In some embodiments, the antibody or target- binding fragment thereof is selected from an anti-FcRn antibody, an anti-MR antibody, an anti-CD205 antibody, an anti-CD169 antibody, an anti-CD14 antibody, an anti-CD36 antibody, an anti-CD5 antibody, an anti -CD71 antibody, an anti-CD38 antibody, or an anti-prohibin antibody.In some embodiments, the polypeptide is a nanobody. In some embodiments, the nanobody is selected from an anti-transferrin nanobody, an anti-HER2 nanobody, or an anti-EGFR nanobody. In someembodiments, the targeting moiety includes a carbohydrate. In some embodiments, the carbohydrate includes a saccharide, disaccharide, or polysaccharide. In some embodiments, the carbohydrate includes mannose, galactose, or glucose. In some embodiments, the carbohydrate includes GalNAc or mannose 6-phosphate. In some embodiments, the carbohydrate includes a mono-, di-, tri-, or tetra-GalNAc. In some embodiments, the carbohydrate is tri-GalNAc.In some embodiments, the targeting moiety includes a lipid. In some embodiments, the lipid includes a fatty acid. In some embodiments, the fatty acid is a saturated, monounsaturated, or polyunsaturated fatty acid. In some embodiments, the fatty acid is a branched or unbranched chain including from 4 to 40 (e.g., 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40) main-chain carbon atoms. In some embodiments, the fatty acid includes squalene, stearic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, lauric acid, docosahexaenoic acid (DHA), docosanoic acid (DCA), eicosapentaenoic acid (EPA), octadecanoic acid, myristic acid, anadamide, a-tocopherol, a-tocopherol succinate, or a retinoic acid. In some embodiments, the fatty acid includes docosanoic acid. In some embodiments, the fatty acid includes docosahexanoic acid. In some embodiments, the fatty acid includes myristic acid. In some embodiments, the lipid includes a steroid or sterol selected from cholesterol, tocopherol, ursodeoxycholic acid, or lithocholic acid. In some embodiments, the steroid or sterol is cholesterol. In some embodiments, the steroid or sterol is tocopherol. In some embodiments, the lipid includes a fat-soluble vitamin selected from vitamin A, vitamin D, vitamin E, vitamin K, or an analog or metabolite thereof. In some embodiments, the lipid includes a phospholipid. In some embodiments, the phospholipid is selected from phosphocholine (PC), PC-docosahexaenoic acid (PC-DHA), PC-docosanoic acid (PC-DCA), PC- eicosapentaenoic acid (PC-EPA), PC-lithocholic acid (PC-LA), PC-retinoic acid (PC-RA), and PC-a- tocopherol succinate (PC-TS).In some embodiments, the targeting moiety includes an oligonucleotide. In some embodiments, the targeting moiety includes an aptamer.In some embodiments, the linker is a bond. In some embodiments, the linker includes 1 to 250 (e.g., 1 to 225, 1 to 200, 1 to 175, 1 to 150, 1 to 125, 1 to 100, 1 to 75, 1 to 50, 1 to 25, 25 to 250, 50 to 250, 75 to 250, 100 to 250, 125 to 250, 150 to 250, 175 to 250, 200 to 250, 225 to 250, 5 to 50, or 5 to 30) backbone atoms, wherein the backbone atoms are selected from C, N, O, and S. In some embodiments, the linker includes an oligonucleotide. In some embodiments, the linker includes a polypeptide. In some embodiments, the linker includes at least one PEG unit. In some embodiments, the. In some embodiments, the linker includes at least one TEG unit. In some embodiments, the TEG is aIn some embodiments, the linker is an enzymatically cleavablelinker. In some embodiments, the linker has a length of at least 0.1 nm. In some embodiments, the linker has a length of from 0.1 nm to 20 nm (e.g., 0.1 nm to 18 nm, 0.1 nm to 16 nm, 0.1 nm to 14 nm, 0.1 nm to 12 nm, 0.1 nm to 10 nm, 0.1 nm to 8 nm, 0.1 nm to 6 nm, 0.1 nm to 4 nm, 0.1 nm to 2 nm, 0.1 nm to 0.5 nm, 0.5 nm to 20 nm, 2 nm to 20 nm, 4 nm to 20 nm, 6 nm to 20 nm, 8 nm to 20 nm, 10 nm to 20 nm, 12 nm to 20 nm, 14 nm to 20 nm, 16 nm to 20 nm, 18 nm to 20 nm, 0.2 nm to 15 nm, or 0.5 nm to 18 nm).In some embodiments, the linker is further conjugated to avidin. In some embodiments, the avidin binds from 1 to 4 (e.g., 1 , 2, 3, or 4) targeting moieties. In some embodiments, the avidin binds from 1 to 4 (e.g., 1 , 2, 3, or 4) targeting moieties, wherein the targeting moieties are conjugated to at least one biotin compound.In some embodiments, X is an oligonucleotide. In some embodiments, the oligonucleotide includes a ribonucleic acid, a deoxyribonucleic acid, a peptide nucleic acid, a locked nucleic acid, or a glycol nucleic acid. In some embodiments, the circular polyribonucleotide is bound to from 1 to 100, 1 to 50, 1 to 20, or 1 to 10 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) oligonucleotides, wherein each oligonucleotide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 2 to 10, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 oligonucleotides wherein each oligonucleotide is complexed to at least one targeting moiety. In some embodiments, the oligonucleotide is from 5 to 100 (e.g., 5 to 80, 5 to 60, 5 to 40, 5 to 20, 20 to 100, 40 to 100, 60 to 100, 80 to 100, 20 to 60, or 10 to 50) nucleotides in length.In some embodiments, the circular polynucleotide includes one or more binding regions each including from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein each binding region binds to an oligonucleotide. In some embodiments, each binding region includes at least 50%, 60%, 70%, 80%, 90%, or 100% complementarity to the oligonucleotide.In some embodiments, X is a polypeptide. In some embodiments, the polypeptide includes an RNA recognition motif wherein the RNA recognition motif is selected from a K homology domain, a zinc finger motif, a Pumilio homology domain, pentatricopeptide repeat domain, pseudouridine synthase and archaeosine transglycosylase domain, a THUMP domain, a YT521 -B homology domain, a double stranded RNA binding domain, a helicase domain, a cold shock domain, an S1 domain, an Sm domain, a La motif, a Piwi-Argonaute-Zwille domain, or an intrinsically disordered region.In some embodiments, the circular polyribonucleotide is bound to from 1 to 100, 1 to 50, 1 to 20, or 1 to 10 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10) polypeptides, wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 polypeptides wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide includes one or more protein binding regions each including from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein each protein binding region binds to a polypeptide. In some embodiments, the circular polyribonucleotide further includes at least one coding region. In some embodiments, the at least one coding region includes an internal ribosomal entry site (IRES) operably linked to an expression sequence encoding a polypeptide. In some embodiments, the polypeptide is expressed in the cell. In some embodiments, the polypeptide is expressed in the cell, optionally wherein the polypeptide expressed in the cell is functional.In some embodiments, the circular polyribonucleotide includes one or more binding regions each including from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein each binding region binds to X. In some embodiments, the binding region iscontained within or overlaps in-part with an expression sequence or with a spacer region. In some embodiments, the binding region is not contained within nor does it overlap in-part with an IRES. In some embodiments, the 3’ end of the binding region is at least 5 ribonucleotides from 5’ end of the IRES; the 3’ end of the binding region is from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides from 5’ end of the IRES; the 5’ end of the binding region is at least 5 ribonucleotides from 3’ end of the IRES; or the 5’ end of the binding region is from 5 to 200 ribonucleotides from 3’ end of the IRES. In some embodiments, the circular polyribonucleotide includes the following elements, arranged in the following order: (i) a first spacer region; (ii) at least one coding region including an internal ribosomal entry site (IRES) operably linked to an expression sequence encoding a polypeptide; (iii) optionally a second spacer region; and (iv) a binding region including from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein the binding region binds to X. In some embodiments, the circular polyribonucleotide includes the following elements, arranged in the following order: (i) a first spacer region; (ii) a target binding region including at least one aptamer or at least ribozyme sequence; (iii) optionally a second spacer region; and (iv) a binding region including from 5 to 200 (e.g., from 5 to 175, 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 25 to 200, 50 to 200, 75 to 200, 100 to 200, 125 to 200, 150 to 200, 175 to 200, 25 to 100, or 50 to 150) ribonucleotides, wherein the binding region binds to X.In some embodiments, the first spacer region includes from 10 to 500 (e.g., from 10 to 450, 10 to 400, 10 to 350, 10 to 300, 10 to 250, 10 to 200, 10 to 150, 10 to 100, 10 to 50, 50 to 500, 100 to 500, 150 to 500, 200 to 500, 250 to 500, 300 to 500, 350 to 500, 400 to 500, 450 to 500, 50 to 150, or 100 to 300) ribonucleotides. In some embodiments, the second spacer region includes 10 to 500 ribonucleotides (e.g., 10 to 450, 10 to 400, 10 to 350, 10 to 300, 10 to 250, 10 to 200, 10 to 150, 10 to 100, 10 to 50, 50 to 500, 100 to 500, 150 to 500, 200 to 500, 250 to 500, 300 to 500, 350 to 500, 400 to 500, 450 to 500, 50 to 150, or 100 to 300).In some embodiments, the binding region is contained within or overlaps in-part with the expression sequence. In some embodiments, the binding region is contained within or overlaps the first spacer region. In some embodiments, the binding region is contained within or overlaps the second spacer region. In some embodiments, the first spacer and second spacer are adjacent to one another. In some embodiments, the binding region overlaps the first and second spacer regions. In some embodiments, the binding region is not contained within nor does it overlap in-part with the expression sequence or with the first or second spacer region.In some embodiments, the circular polyribonucleotide includes at least 1 ,000 ribonucleotides. In some embodiments, the circular polyribonucleotide includes at least 3,000 ribonucleotides. In some embodiments, the circular polyribonucleotide includes from 1 ,000 to 20,000 (e.g., from 1 ,000 to 18,000; 1 ,000 to 16,000; 1 ,000 to 14,000; 1 ,000 to 12,000; 1 ,000 to 10,000; 1 ,000 to 8,000; 1 ,000 to 6,000; 1 ,000 to 4,000; 1 ,000 to 2,000; 2,000 to 20,000; 4,000 to 20,000; 6,000 to 20,000; 8,000 to 20,000; 10,000 to 20,000; 12,000 to 20,000; 14,000 to 20,000; 16,000 to 20,000; 18,000 to 20,000; 5,000 to 10,000; or 3,000 to 12,000) ribonucleotides.In some embodiments, the circular polyribonucleotide encodes a polypeptide. In some embodiments, the polypeptide is a eukaryotic polypeptide. In some embodiments, the polypeptide is amammalian polypeptide. In some embodiments, the polypeptide is a mammalian polypeptide, optionally wherein the polypeptide is a human polypeptide. In some embodiments, the polypeptide is a viral, bacterial, or fungal polypeptide. In some embodiments, the polypeptide is for therapeutic use. In some embodiments, the polypeptide is an immunogen.In some embodiments, the circular polyribonucleotide includes an IRES. In some embodiments, the IRES is selected from an IRES sequence of Taura syndrome virus, Triatoma virus, Theiler's encephalomyelitis virus, simian Virus 40, Solenopsis invicta virus 1 , Rhopalosiphum padi virus, Reticuloendotheliosis virus, fuman poliovirus 1 , Plautia stall intestine virus, Kashmir bee virus, Human rhinovirus 2, Homalodisca coagulata virus- 1 , Human Immunodeficiency Virus type 1 , Homalodisca coagulata virus- 1 , Himetobi P virus, Hepatitis C virus, Hepatitis A virus, Hepatitis GB virus, foot and mouth disease virus, Human enterovirus 71 , Equine rhinitis virus, Ectropis obliqua picoma-like virus, Encephalomyocarditis virus (EMCV), Drosophila C Virus, Crucifer tobamo virus, Cricket paralysis virus, Bovine viral diarrhea virus 1 , Black Queen Cell Virus, Aphid lethal paralysis virus, Avian encephalomyelitis virus, Acute bee paralysis virus, Hibiscus chlorotic ringspot virus, Classical swine fever virus, Human FGF2, Human SFTPA1 , Human AML1 / RUNX1 , Drosophila antennapedia, Human AQP4, Human AT1 R, Human BAG-I, Human BCL2, Human BiP, Human c-IAPI , Human c- myc, Human elF4G, Mouse NDST4L, Human LEF1 , Mouse HIF1 alpha, Human n.myc, Mouse Gtx, Human p27kipl, Human PDGF2 / c-sis, Human p53, Human Pim-I, Mouse Rbm3, Drosophila reaper, Canine Scamper, Drosophila Ubx, Salivirus, Cosavirus, Parechovirus, Human UNR, Mouse UtrA, Human VEGF-A, Human XIAP, Drosophila hairless, S. cerevisiae TFIID, S. cerevisiae YAP1 , Human c-src, Human FGF-I, Simian picomavirus, Turnip crinkle virus, Coxsackievirus B3 (CVB3) or Coxsackievirus A (CVB1 / 2).In an aspect, the disclosure provides a pharmaceutical composition including any one of the circular polyribonucleotides described herein and one or more delivery agents. In some embodiments, the delivery agent is selected from calcium, magnesium, manganese, or strontium. In some embodiments, the delivery agent is an endosomal escape agent. In some embodiments, the endosomal escape agent includes chloroquine, amantadine, ammonium chloride, 4-bromobenzaldehyde N-(2,6- dimethylphenyl)semicarbazone (EGA), UNC-108, or any combination thereof. In some embodiments, the delivery agent is a globular protein. In some embodiments, the globular protein is albumin. In some embodiments, the delivery agent is ribonuclease inhibitor.In another aspect, the disclosure provides a method of delivering a circular polyribonucleotide to a cell, the method including contacting the cell with any one of the complexes or pharmaceutical compositions described herein. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the circular polyribonucleotide is delivered to the cell ex-vivo. In some embodiments, the cell is administered to a subject after the delivery of the circular polyribonucleotide to the cell. In some embodiments, administration of the cell to the subject treats a disease, disorder, or condition in the subject.In an aspect, the disclosure provides a method of delivering a circular polyribonucleotide to a subject, the method including administering to the subject any one of the complexes or pharmaceutical compositions described herein.In another aspect, the disclosure provides a method of treating a disease, disorder, or condition in a subject, the method including administering to the subject any one of the complexes or pharmaceutical compositions described herein.In another aspect, the disclosure provides a method of inducing an immune response in a subject, the method including administering to the subject any one of the complexes or pharmaceutical compositions described herein. In some embodiments, the complex or pharmaceutical composition is administered intramuscularly, subcutaneously, intravenously, intraperitoneally, topically, or orally.In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal. In some embodiments, the non-human mammal is a cow, a sheep, a goat, a pig, a dog, a horse, or a cat. In some embodiments, the subject is a bird. In some embodiments, the bird is a hen, a rooster, a turkey, or a parrot.In an aspect, the disclosure provides a method of covalently attaching a targeting moiety to a circular polyribonucleotide. The method includes forming a complex as described herein (e.g., of any of the above embodiments) and irradiating the complex with light. In some embodiments, the wavelength of the irradiated light is from 350-370 (e.g., 350, 351 , 352, 353. 354, 355, 356, 357, 358, 359, 360, 361 , 362, 363, 364, 365, 366, 367, 368, 369, or 370) nm. In some embodiments, the complex is irradiated for 1 to 120 (e.g., 1 , 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120) minutes.In another aspect, the disclosure provides a method of removing the covalent attachment between the circular polyribonucleotide and the moiety that binds specifically to a region of the circular polyribonucleotide and includes one or more photoreactive crosslinking agent. The method includes irradiating any one of the complexes described herein with light at a second wavelength. In some embodiments, the second wavelength of the irradiated light is from 300-320 (e.g., 300, 301 , 302, 303, 304, 305, 306, 307, 308, 309, 310, 311 , 312, 313, 314, 315, 316, 317, 318, 319, or 320) nm. In some embodiments, the complex is irradiated at the second wavelength for 1 to 120 (e.g., 1 , 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120) minutes.In another aspect, the disclosure provides a method of delivering a circular polyribonucleotide to a cell. The method includes contacting the cell with any one of the complexes or pharmaceutical compositions described herein. In some embodiments, the complex is irradiated prior to contacting the cell. In some embodiments, the complex is irradiated after contacting the cell. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the circular polyribonucleotide is delivered to the cell ex-vivo. In some embodiments, the complex is delivered to the cell in-vivo. In some embodiments, the cell is administered to a subject after the delivery of the circular polyribonucleotide to the cell. In some embodiments, the complex is irradiated prior to administration to the subject. In some embodiments, the complex is irradiated after administration to the subject. In some embodiments, administration of the cell to the subject treats a disease, disorder, or condition in the subject.In an aspect, the disclosure provides a method of delivering a circular polyribonucleotide to a subject. The method includes administering to the subject any one of the complexes or pharmaceutical compositions described herein.In another aspect, the disclosure provides a method of treating a disease, disorder, or condition in a subject. The method includes administering to the subject any one of the complexes or pharmaceutical compositions described herein.In another aspect, the disclosure provides a covalent complex produced by any of the methods described herein.DefinitionsTo facilitate the understanding of this disclosure, several terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the disclosure. Terms such as "a," "an," and "the" are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The term "or" is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or”. The terminology herein is used to describe specific embodiments, but their usage is not to be taken as limiting, except as outlined in the claims.As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.As used herein, the term “about” refers to a value that is within ± 10% of a recited value.The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, and antibody fragments so long as they exhibit the desired antigen-binding activity. An "antibody fragment" refers to a molecule other than an intact antibody that includes a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and single-domain antibodies. For a review of certain antibody fragments, see Hudson et al., Nat Med 9, 129- 134 (2003). For a review of scFv fragments, see e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); see also WO 93 / 16185; and U.S. Patent Nos. 5,571 ,894 and 5,587,458. For discussion of Fab and F(ab')2 fragments including salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046. Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01161 ; Hudson et al., Nat Med 9, 129-134 (2003); and Hollinger et al., Proc Natl Acad Sci USA 90, 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat Med 9, 129-134 (2003). Single-domain antibodies are antibody fragments including all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single- domain antibody. Antibody fragments can be made by various techniques.As used herein, the term “aptamer” is a non-naturally occurring or synthetic oligonucleotide that specifically binds to a target molecule. Typically, an aptamer is from 20 to 500 nucleotides. Typically, an aptamer binds to its target through secondary structure rather than sequence homology.As used herein, the term “binding moiety” refers to a moiety that specifically binds to (e.g., hybridized or hybridized and covalently bound to) a portion of the circular polyribonucleotide. The binding moiety may include one or more photoreactive crosslinking agents.As used herein, the term “binding region” refers to a portion of the circular polyribonucleotide to which one or more moieties specifically bind. The one or more moieties specifically bind to the portion of the circular polyribonucleotides by non-covalent interactions. For example, an oligonucleotide may anneal to the binding region by way of hydrogen bonds, or a polypeptide may bind to a binding region by way of hydrogen bonds, hydrophobic interactions, or Van der Waals interactions.As used herein, the term “carrier” is a compound, composition, reagent, or molecule that facilitates the transport or delivery of a composition (e.g., a circular polyribonucleotide) into a cell by a covalent modification of the circular polyribonucleotide, via a partially or completely encapsulating agent, or a combination thereof. Non-limiting examples of carriers include carbohydrate carriers (e.g., an anhydride-modified phytoglycogen or glycogen-type material), nanoparticles (e.g., a nanoparticle that encapsulates or is covalently linked binds to the circular polyribonucleotide), liposomes, fusosomes, ex vivo differentiated reticulocytes, exosomes, protein carriers (e.g., a protein covalently linked to the circular polyribonucleotide), or cationic carriers (e.g., a cationic lipopolymer or transfection reagent).As used herein, the term “cell-penetrating peptide” refers to a peptide having from about 5 to about 30 amino acids residues which has a net positive charge, which facilitate penetration into cells across the cell membrane.As used herein, the terms “circular polyribonucleotide” and “circular RNA” are used interchangeably and mean a polyribonucleotide molecule that has a structure having no free ends (i.e. , no free 3’ or 5’ ends), for example a polyribonucleotide molecule that forms a circular or end-less structure through covalent or non-covalent bonds. The circular polyribonucleotide may be, e.g., a covalently closed polyribonucleotide.As used herein, the term “circularization efficiency” is a measurement of resultant circular polyribonucleotide versus its non-circular starting material.As used herein, the term “coding region” refers to a region of the polynucleotide including an expression sequence encoding a polypeptide and an IRES and / or another regulatory element.As used herein, the term “crosslink” refers to forming a covalent bond between two molecules. For example, a photoactivatable crosslinking agent may form a crosslink between the agent and a ribonucleotide upon irradiation with light.As used herein, the term “delivery agent” refers to an agent that, when added to the pharmaceutical composition including the circular polyribonucleotides described herein, increases cellular delivery, functional delivery, or endosomal escape of the circular polyribonucleotide relative to the same pharmaceutical composition that lacks the agent. The increase in cellular delivery, functional delivery, or endosomal escape of the circular polyribonucleotide may be measured, e.g., by assessing the amount of expression of a polypeptide encoded by the circular polyribonucleotide in comparison to a pharmaceutical composition that does not include the delivery agent.The term “derived from” refers to in the present specification in the context of a nucleic acid, i.e., for a nucleic acid “derived from” (another) nucleic acid, means that the nucleic acid, which is derived from (another) nucleic acid, shares e.g. at least 60%, 70%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the nucleic acid from which it is derived. The skilled person is aware that sequence identity is typically calculated for the same types of nucleic acids, i.e., for DNA sequences or for RNA sequences. Thus, it is understood, if a DNA is “derived from” an RNA or if an RNA is “derived from” a DNA, in a first step the RNA sequence is converted into the corresponding DNA sequence (in particular by replacing the uracils (U) by thymidines (T) throughout the sequence) or, vice versa, the DNA sequence is converted into the corresponding RNA sequence (in particular by replacing the T by U throughout the sequence). Thereafter, the sequence identity of the DNA sequences or the sequence identity of the RNA sequences is determined. Preferably, a nucleic acid “derived from” a nucleic acid also refers to nucleic acid, which is modified in comparison tothe nucleic acid from which it is derived, e.g., in order to increase RNA stability even further and / or to prolong and / or increase protein production. In the context of amino acid sequences, the term “derived from” means that the amino acid sequence, which is derived from (another) amino acid sequence, shares e.g. at least 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence from which it is derived.The term “diluent” means a vehicle including an inactive solvent in which a composition described herein (e.g., a composition including a circular polyribonucleotide) may be diluted or dissolved. A diluent can be an RNA solubilizing agent, a buffer, an isotonic agent, or a mixture thereof. A diluent can be a liquid diluent or a solid diluent. Non-limiting examples of liquid diluents include water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetra hydrofurfury I alcohol, polyethylene glycols and fatty acid esters of sorbitan, and 1 ,3-butanediol. Non-limiting examples of solid diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, or powdered sugar.As used herein, the terms “disease,” “disorder,” and “condition” each refer to a state of sub- optimal health, for example, a state that is or would typically be diagnosed or treated by a medical professional.As used herein, the term “expression sequence” is a nucleic acid sequence that encodes a product, e.g., a peptide or polypeptide, beginning with a start codon and ending with a stop codon. An exemplary expression sequence that codes for a peptide or polypeptide can include a plurality of nucleotide triads, each of which can code for an amino acid and is termed as a “codon.”As used herein, the term “fragment” with respect to a polypeptide or a nucleic acid sequence refers to a continuous, less than a whole portion of a sequence of the polypeptide or the nucleic acid. A fragment of a polypeptide or a nucleic acid sequence encoding a polypeptide, for instance, refers to continuous, less than a whole fraction (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the entire length) of the sequence such as a sequence disclosed herein.As used herein, the term “functional delivery” refers to delivery of a polyribonucleotide encoding a polypeptide into a cell, wherein the polypeptide is expressed in the cell.By “heterologous” is meant to occur in a context other than in the naturally occurring (native) context. A “heterologous” polynucleotide sequence indicates that the polynucleotide sequence is being used in a way other than what is found in that sequence’s native genome. For example, a “heterologous promoter” is used to drive transcription of a sequence that is not one that is natively transcribed by that promoter; thus, a “heterologous promoter” sequence is often included in an expression construct by means of recombinant nucleic acid techniques. The term "heterologous" is also used to refer to a given sequence that is placed in a non-naturally occurring relationship to another sequence; for example, a heterologous coding or non-coding nucleotide sequence is commonly inserted into a genome by genomic transformation techniques, resulting in a genetically modified or recombinant genome.As used herein, the term “linear counterpart” is a polyribonucleotide molecule (and its fragments) having the same or similar nucleotide sequence (e.g., 100%, 95%, 90%, 85%, 80%, 75%, or any percentage therebetween sequence identity) as a circular polyribonucleotide and having two free ends (i.e., the uncircularized version (and its fragments) of the circularized polyribonucleotide). In some embodiments, the linear counterpart (e.g., a pre-circularized version) is a polyribonucleotide molecule (and its fragments) having the same or similar nucleotide sequence (e.g., 100%, 95%, 90%, 85%, 80%, 75%, or any percentage therebetween sequence identity) and same or similar nucleic acid modifications as a circular polyribonucleotide and having two free ends (i.e., the uncircularized version (and its fragments) of the circularized polyribonucleotide). In some embodiments, the linear counterpart is a polyribonucleotide molecule (and its fragments) having the same or similar nucleotide sequence (e.g., 100%, 95%, 90%, 85%, 80%, 75%, or any percentage therebetween sequence identity) and different or no nucleic acid modifications as a circular polyribonucleotide and having two free ends (i.e., the uncircularized version (and its fragments) of the circularized polyribonucleotide). In some embodiments, a fragment of the polyribonucleotide molecule that is the linear counterpart is any portion of linear counterpart polyribonucleotide molecule that is shorter than the linear counterpart polyribonucleotide molecule. In some embodiments, the linear counterpart further includes a 5’ cap. In some embodiments, the linear counterpart further includes a poly adenosine tail. In some embodiments, the linear counterpart further includes a 3’ UTR. In some embodiments, the linear counterpart further includes a 5’ UTR.As used herein, the terms “linear RNA,” “linear polyribonucleotide,” and “linear polyribonucleotide molecule” are used interchangeably and mean polyribonucleotide molecule having a 5’ and 3’ end. One or both of the 5’ and 3’ ends may be free ends or joined to another moiety. Linear RNA includes RNA that has not undergone circularization (e.g., is pre-circularized) and can be used as a starting material for circularization.As used herein, the term “linker” refers to a covalent linkage or connection between two or more components in a conjugate (e.g., between a polyribonucleotide or oligonucleotide and a lipid moiety and a PEG, as described herein). Molecules that may be used as linkers include at least two functional groups, which may be the same or different, e.g., two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and a maleimide group, a carboxylic acid group and an alkyne group, a carboxylic acid group and an amine group, a carboxylic acid group and a sulfonic acid group, an amine group and a maleimide group, an amine group and an alkyne group, or an amine group and a sulfonic acid group. The first functional group may form a covalent linkage with a first component in the conjugate and the second functional group may form a covalent linkage with the second component in the conjugate. A linker typically provides space, rigidity, and / or flexibility between the two or more components.As used herein, the terms “lipid” or “lipid moiety” refer to organic compounds, most preferably organic biomolecules, that are selectively soluble in nonpolar solvents over water. Lipid moieties specifically contemplated by the present invention include, for example, fatty acids, steroids or sterols, glycerides (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids, and fat-soluble vitamins (e.g., vitamins A, D, E, and K).As used herein, the term “modified ribonucleotide” means a nucleotide with at least one modification to the sugar, the nucleobase, or the internucleoside linkage.As used herein, the term “naked delivery” is a formulation for delivery to a cell without the aid of a carrier and without covalent modification to a moiety that aids in delivery to a cell. A naked delivery formulation is free from any transfection reagents, cationic carriers, carbohydrate carriers, nanoparticle carriers, or protein carriers. For example, naked delivery formulation of a circular polyribonucleotide is a formulation that includes a circular polyribonucleotide without covalent modification and is free from a carrier.As used herein, the term “nanobody” refers to a polypeptide having a single monomeric variable domain and has a molecular weight of between about 12 kDa and about 15 kDa. A nanobody is able to selectively bind to a specific antigen.The term “photoreactive crosslinking agent”, as used herein, refers to any compound that is configured to form a covalent adduct with another molecule upon irradiation with light. For example, a photoreactive crosslinking agent may covalently attach to a ribonucleotide within the circular polyribonucleotide upon irradiation with light. In embodiments, a photoreactive crosslinking agent may be able to form a covalent attachment to a ribonucleotide within the circular polyribonucleotide that is reversible. In embodiments, the photoreactive crosslinking agent can be a photoreactive nucleotide analog or photoreactive amino acid analog.The term “photoreactive nucleotide analog” refers to any nucleic acid analog that is configured to form a covalent adduct with another molecule upon irradiation with light. For example, the photoreactive nucleotide analog may be present within an oligonucleotide and be configured to covalently attach to a circular polyribonucleotide upon irradiation with light. In some embodiments, the photoreactive nucleotide analog can covalently attach to a complementary ribonucleotide or a ribonucleotide located 1 base upstream or 1 base downstream of a complementary ribonucleotide within the circular polyribonucleotide upon photoirradiation. Examples of photoreactive nucleotide analogs include, but are not limited to, 4- thiouridene (4sU), 5-bromo-2’-deoxyuridine (BrdU), coumarin derivatives, 3-cyanovinylcarbazole D- threoninol (cnvD) derivatives, 3-cyanovinylcarbazole nucleoside (CNVK) derivatives, diazirene derivatives, phenylselenide derivatives, psoralen derivatives, or pyranocarbazole (PCX) derivatives. For a review of certain photoreactive nucleotide analogs, see Elskens et al., RSC Chem. Biol. 2, 410-422, 2021 and Tavakoli et al., RSC Adv. 12, 6484-6507, 2022. In embodiments, the covalent attachment of the photoreactive nucleotide analog to the ribonucleotide is reversible, e.g., it may be removed when irradiated with light, e.g., of a second different wavelength.The term “photoreactive amino acid analog” refers to any amino acid analog that is configured to form a covalent adduct with another molecule upon irradiation with light. For example, the photoreactive amino acid analog may be present within a polypeptide that covalently attaches to a circular polyribonucleotide upon irradiation with light. In some embodiments, the photoreactive amino acid analog can covalently attach to a nearby ribonucleotide within the circular polyribonucleotide upon photoirradiation. Examples of photoreactive amino acid analogs include but are not limited to diazirene- based, aryl azide-based, benzophenone-based unnatural amino acid, or A / -e-[2-(furan-2- yl)ethoxy]carbonyl-lysine. In embodiments, the covalent attachment of the photoreactive amino acid analog to the ribonucleotide is reversible, e.g., it may be removed when irradiated with light, e.g., a second different wavelength.The term “pharmaceutical composition” is intended to also disclose that the circular or linear polyribonucleotide included within a pharmaceutical composition can be used for the treatment of thehuman or animal body by therapy. It is thus meant to be equivalent to “a polyribonucleotide for use in therapy.”The term “polynucleotide,” as used herein, means a molecule including one or more nucleic acid subunits, or nucleotides, and can be used interchangeably with “nucleic acid” or “oligonucleotide”. A polynucleotide can include one or more nucleotides selected from adenosine (A), cytosine (C), guanine (G), thymine (T) and uracil (U), or variants thereof. A nucleotide can include a nucleoside and at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more phosphate (PO3) groups. A nucleotide can include a nucleobase, a five- carbon sugar (either ribose or deoxyribose), and one or more phosphate groups. Ribonucleotides are nucleotides in which the sugar is ribose. Polyribonucleotides or ribonucleic acids, or RNA, can refer to macromolecules that include multiple ribonucleotides that are polymerized via phosphodiester bonds. Deoxyribonucleotides are nucleotides in which the sugar is deoxyribose.As used herein, the term “polyribonucleotide cargo” herein includes any sequence including at least one polyribonucleotide. In embodiments, the polyribonucleotide cargo includes one or multiple expression sequences, wherein each expression sequence encodes a polypeptide. In embodiments, the polyribonucleotide cargo includes one or multiple noncoding sequences, such as a polyribonucleotide having regulatory or catalytic functions. In embodiments, the polyribonucleotide cargo includes a combination of expression and noncoding sequences. In embodiments, the polyribonucleotide cargo includes one or more polyribonucleotide sequence described herein, such as one or multiple regulatory elements, internal ribosomal entry site (IRES) elements, or spacer sequences.As used interchangeably herein, the terms “polyA,” “polyA sequence,” and “polyA tail” refer to an untranslated, contiguous region of a nucleic acid molecule of at least 5 nucleotides in length and consisting of adenosine residues. In some embodiments, a polyA tail is at least 10, at least 15, at least 20, at least 30, at least 40, or at least 50 nucleotides in length. In some embodiments, a polyA tail is located 3’ to (e.g., downstream of) an open reading frame (e.g., an open reading frame encoding a polypeptide), and the polyA tail is 3’ to a termination element (e.g., a stop codon) such that the polyA is not translated. In some embodiments, a polyA tail is located 3’ to a termination element and a 3’ untranslated region.As used herein, the elements of a nucleic acid are “operably connected” if they are positioned on the vector such that they can be transcribed to form a linear RNA that can then be circularized into a circular RNA using the methods provided herein.“Polydeoxyribonucleotides,” “deoxyribonucleic acids,” and “DNA” mean macromolecules that include multiple deoxyribonucleotides that are polymerized via phosphodiester bonds. A nucleotide can be a nucleoside monophosphate or a nucleoside polyphosphate. A nucleotide means a deoxyribonucleoside polyphosphate, such as, e.g., a deoxyribonucleoside triphosphate (dNTP), which can be selected from deoxyadenosine triphosphate (dATP), deoxycytidine triphosphate (dCTP), deoxyguanosine triphosphate (dGTP), uridine triphosphate (dUTP) and deoxythymidine triphosphate (dTTP) dNTPs, that include detectable tags, such as luminescent tags or markers (e.g., fluorophores). A nucleotide can include any subunit that can be incorporated into a growing nucleic acid strand. Such subunit can be an A, C, G, T, or U, or any other subunit that is specific to one or more complementary A, C, G, T or U, or complementary to a purine (i.e., A or G, or variant thereof) or a pyrimidine (i.e., C, T or U, or variant thereof). In some examples, a polynucleotide is deoxyribonucleic acid (DNA), ribonucleic acid (RNA), or derivatives or variants thereof. In some cases, a polynucleotide is a short interfering RNA(siRNA), a microRNA (miRNA), a plasmid DNA (pDNA), a short hairpin RNA (shRNA), small nuclear RNA (snRNA), messenger RNA (mRNA), precursor mRNA (pre-mRNA), antisense RNA (asRNA), to name a few, and encompasses both the nucleotide sequence and any structural embodiments thereof, such as single-stranded, double-stranded, triple-stranded, helical, hairpin, etc. In some cases, a polynucleotide molecule is circular. A polynucleotide can have various lengths. A nucleic acid molecule can have a length of at least about 10 bases, 20 bases, 30 bases, 40 bases, 50 bases, 100 bases, 200 bases, 300 bases, 400 bases, 500 bases, 1 kilobase (kb), 2 kb, 3, kb, 4 kb, 5 kb, 10 kb, 50 kb, or more. A polynucleotide can be isolated from a cell or a tissue. As embodied herein, the polynucleotide sequences may include isolated and purified DNA / RNA molecules, synthetic DNA / RNA molecules, and synthetic DNA / RNA analogs.Polynucleotides, e.g., polyribonucleotides or polydeoxyribonucleotides, may include one or more nucleotide variants, including nonstandard nucleotide(s), non-natural nucleotide(s), nucleotide analog(s) and / or modified nucleotides. Examples of modified nucleotides include, but are not limited to diaminopurine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4- acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6- isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2- methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5- methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'- methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6 -isopentenyladenine, uracil-5-oxyacetic acid, wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4- thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid(v), 5-methyl-2- thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, 3-(3-amino-3-carboxypropyl)uridine 2,6-diaminopurine and the like. In some cases, nucleotides may include modifications in their phosphate moieties, including modifications to a triphosphate moiety. Non-limiting examples of such modifications include phosphate chains of greater length (e.g., a phosphate chain having, 4, 5, 6, 7, 8, 9, 10 or more phosphate moieties) and modifications with thiol moieties (e.g., alpha-thiotriphosphate and beta-thiotriphosphates). Nucleic acid molecules may also be modified at the base moiety (e.g., at one or more atoms that typically are available to form a hydrogen bond with a complementary nucleotide and / or at one or more atoms that are not typically capable of forming a hydrogen bond with a complementary nucleotide), sugar moiety or phosphate backbone. Nucleic acid molecules may also contain amine -modified groups, such as amino ally 1-dUTP (aa-dUTP) and aminohexhylacrylamide-dCTP (aha-dCTP) to allow covalent attachment of amine reactive moieties, such as N-hydroxysuccinimide esters (NHS). Alternatives to standard DNA base pairs or RNA base pairs in the oligonucleotides of the present disclosure can provide higher density in bits per cubic mm, higher safety (resistant to accidental or purposeful synthesis of natural toxins), easier discrimination in photo-programmed polymerases, or lower secondary structure. Such alternative base pairs compatible with natural and mutant polymerases for de novo and / or amplification synthesis are described in Betz K, Malyshev DA, Lavergne T, Welte W, Diederichs K, Dwyer TJ, Ordoukhanian P, Romesberg FE, Marx A. Nat. Chem. Biol. 2012 Jul;8(7):612-4, which is herein incorporated by reference for all purposes.As used herein, “polypeptide” means a polymer of amino acid residues (natural or unnatural) linked together most often by peptide bonds. The term, as used herein, refers to proteins, polypeptides,and peptides of any size, structure, or function. Polypeptides can include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing. A polypeptide can be a single molecule or a multi- molecular complex such as a dimer, trimer, or tetramer. They can also include single chain or multichain polypeptides such as antibodies or insulin and can be associated or linked. 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.As used herein, the term “prevent” means to reduce the likelihood of developing a disease, disorder, or condition, or alternatively, to reduce the severity or frequency of symptoms in a subsequently developed disease or disorder. A therapeutic agent can be administered to a subject who is at increased risk of developing a viral infection relative to a member of the general population in order to prevent the development of, or lessen the severity of, the disease or condition. A therapeutic agent can be administered as a prophylactic, e.g., before development of any symptom or manifestation of a viral infection.As used herein, the term “regulatory element” is a moiety, such as a nucleic acid sequence, that modifies expression of an expression sequence within the circular or linear polyribonucleotide.As used herein, the term “replication element” is a sequence and / or motif useful for replication or that initiate transcription of the circular polyribonucleotide.As used herein, the term “small molecule” refers to a low molecular weight compound (e.g., a compound (e.g., an organic compound) having less than 1000 Da, that may regulate a biological process, with a size on the order of 1 nm. In some instances, a therapeutic agent is a small molecule therapeutic agent. In some instances, the small molecule agent is from about 300 to about 700 Da (e.g., about 325 Da, about 350 Da, about 375 Da, about 400 Da, about 425 Da, about 450 Da, about 475 Da, about 500 Da, about 525 Da, about 550 Da, about 575 Da, about 600 Da, about 625 Da, about 650 Da, or about 675 Da).As used herein, a “spacer” refers to any contiguous nucleotide sequence (e.g., of one or more nucleotides) that provides distance or flexibility between two adjacent polynucleotide regions.A “signal sequence” refers to a polypeptide sequence, e.g., from 10 to 45 amino acids in length, that is present at the N-terminus of a polypeptide sequence of a nascent protein which targets the polypeptide sequence to the secretory pathway.As used herein, the term “sequence identity” is determined by alignment of two peptide or two nucleotide sequences using a global or local alignment algorithm. Sequences are referred to as "substantially identical” or “essentially similar” when they share at least a certain minimal percentage of sequence identity when optimally aligned (e.g., when aligned by programs such as GAP or BESTFIT using default parameters). GAP uses the Needleman and Wunsch global alignment algorithm to align two sequences over their entire length, maximizing the number of matches and minimizes the number of gaps. Generally, the GAP default parameters are used, with a gap creation penalty = 50 (nucleotides) / 8 (proteins) and gap extension penalty = 3 (nucleotides) / 2 (proteins). For nucleotides the default scoring matrix used is nwsgapdna, and for proteins the default scoring matrix is Blosum62 (Henikoff & Henikoff, 1992, PNAS 89, 915-919). Sequence alignments and scores for percentage sequence identity are determined, e.g., using computer programs, such as the GCG Wisconsin Package, Version 10.3,available from Accelrys Inc., 9685 Scranton Road, San Diego, CA 92121-3752 USA, or EmbossWin version 2.10.0 (using the program “needle”). Alternatively, or additionally, percent identity is determined by searching against databases, e.g., using algorithms such as FASTA, BLAST, etc. Sequence identity refers to the sequence identity over the entire length of the sequence.As used herein, the term "subject" refers to an organism, such as an animal, plant, or microbe. In embodiments, the subject is a vertebrate animal (e.g., mammal, bird, fish, reptile, or amphibian). In embodiments, the subject is a human. In embodiments, the subject is a non-human mammal. In embodiments, the subject is a non-human mammal such as a non-human primate (e.g., monkeys, apes), ungulate (e.g., cattle, buffalo, bison, sheep, goat, pig, camel, llama, alpaca, deer, horses, donkeys), carnivore (e.g., dog, cat), rodent (e.g., rat, mouse), or lagomorph (e.g., rabbit). In embodiments, the subject is a bird, such as a member of the avian taxa Galliformes (e.g., chickens, turkeys, pheasants, quail), Anseriformes (e.g., ducks, geese), Paleaognathae (e.g., ostriches, emus), Columbiformes (e.g., pigeons, doves), or Psittaciformes (e.g., parrots). In embodiments, the subject is an invertebrate such as an arthropod (e.g., insects, arachnids, crustaceans), a nematode, an annelid, a helminth, or a mollusk. In embodiments, the subject is an invertebrate agricultural pest or an invertebrate that is parasitic on an invertebrate or vertebrate host. In embodiments, the subject is a plant, such as an angiosperm plant (which can be a dicot or a monocot) or a gymnosperm plant (e.g., a conifer, a cycad, a gnetophyte, a Ginkgo), a fern, horsetail, clubmoss, or a bryophyte. In embodiments, the subject is a eukaryotic alga (unicellular or multicellular). In embodiments, the subject is a plant of agricultural or horticultural importance, such as row crop plants, fruit-producing plants and trees, vegetables, trees, and ornamental plants including ornamental flowers, shrubs, trees, groundcovers, and turf grasses.As used here, the term “targeting moiety” refers to a moiety that binds specifically to a cell or a portion thereof (e.g., an extracellular, intracellular, or membrane portion thereof) thereby promoting intracellular delivery of the moiety and any cargo bound or complexed thereto (e.g., a polyribonucleotide). A targeting moiety may include a lipid, a small molecule, a carbohydrate, a polypeptide, a nucleic acid (e.g., an aptamer), or a combination thereof. In some embodiments, a targeting moiety interacts with the cellular membrane thereby promoting intracellular delivery. In some embodiments, a targeting moiety promotes endosomal delivery and / or endosomal escape. In some embodiments a targeting moiety promotes cellular delivery that is not specific to any cell type. In some embodiments, the targeting moiety binds preferentially to a particular cell type and therefore promotes cell-type specific delivery.As used herein, the term “termination element” is a moiety, such as a nucleic acid sequence, that terminates translation of the expression sequence in the circular or linear polyribonucleotide.As used herein, the term “translation efficiency” is a rate or amount of protein or peptide production from a ribonucleotide transcript. In some embodiments, translation efficiency can be expressed as amount of protein or peptide produced per given amount of transcript that codes for the protein or peptide, e.g., in a given period of time, e.g., in a given translation system, e.g., a cell-free translation system like rabbit reticulocyte lysate.As used herein, the term “translation initiation sequence” is a nucleic acid sequence that initiates translation of an expression sequence in the circular or linear polyribonucleotide.As used herein, the terms “treat” and “treating” refer to a therapeutic treatment of a disease or disorder (e.g., an infectious disease, a cancer, a toxicity, or an allergic reaction) in a subject. The effect of treatment can include reversing, alleviating, reducing severity of, curing, inhibiting the progression of,reducing the likelihood of recurrence of the disease or one or more symptoms or manifestations of the disease or disorder, stabilizing (i.e., not worsening) the state of the disease or disorder, and / or preventing the spread of the disease or disorder as compared to the state and / or the condition of the disease or disorder in the absence of the therapeutic treatment.As used herein, a ’’vector" means a polynucleotide (e.g., DNA) that is synthesized (e.g., using PCR), or that is taken from a virus, plasmid, or cell of a higher organism into which a foreign DNA fragment can be or has been inserted for cloning or expression purposes. In some embodiments, a vector can be stably maintained in an organism. A vector can include, for example, an origin of replication, a selectable marker or reporter gene, such as antibiotic resistance or GFP, or a multiple cloning site (MCS) . The term includes linear DNA fragments (e.g., PCR products, linearized plasmid fragments), plasmid vectors, viral vectors, cosmids, bacterial artificial chromosomes (BACs), yeast artificial chromosomes (YACs), and the like. In one embodiment, the vectors provided herein include a multiple cloning site (MCS). In another embodiment, the vectors provided herein do not include an MCS.Brief Description of the DrawingsFIG. 1 is a schematic of an exemplary circular polyribonucleotide complexed with Xn(L-B)z, where X is a moiety that binds specifically to a region of the circular polyribonucleotide, L is a linker, and B is a targeting moiety, wherein n is 2, and wherein z is 1 in this schematic.FIG. 2 is a schematic of a circular polyribonucleotide having an annealing or binding region in the spacer region and / or an annealing or binding region in the coding region.FIG. 3 is schematic of a circular polyribonucleotide bound to an oligonucleotide covalently linked to a trivalent GalNAc moiety. The oligonucleotide-linker-trivalent GalNAc is bound to either the spacer region or the coding region of the circular polyribonucleotide.FIG. 4 shows the amount of luminescence measured from circular polyribonucleotides encoding a luciferase polypeptide bound to one or two targeting moieties in comparison to a circular polyribonucleotide without a targeting moiety, wherein the targeting moieties are GalNAc (A or B), cholesterol (I), tocopherol (Q), or a combination thereof.FIG. 5 shows the amount of luminescence measured from circular polyribonucleotides encoding a luciferase polypeptide bound to one or two targeting moieties in comparison to a circular polyribonucleotide without a targeting moiety, wherein the targeting moieties are GalNAc (B or C), cholesterol (I or J), tocopherol (Q or R), or a combination thereof.FIG. 6 shows the amount of luminescence measured for circular polyribonucleotides from circular polyribonucleotides encoding a luciferase polypeptide bound to a GalNAc and / or tocopherol targeting moiety in the presence of a ribonuclease inhibitor and / or various concentration of calcium chloride in comparison to a circular polyribonucleotide without a targeting moiety.FIG. 7 shows the amount of luminescence measured from circular polyribonucleotides encoding a luciferase polypeptide bound to one or two targeting moieties in comparison to a circular polyribonucleotide without a targeting moiety, wherein the targeting moieties are GalNAc, cholesterol, or tocopherol in the absence of calcium chloride.FIG. 8A and FIG. 8B shows the amount of luminescence measured for circular polyribonucleotides encoding a luciferase polypeptide bound to a GalNAc and tocopherol targeting moiety in the presence of or absence of BSA in a 1 :1 ratio with the circular polyribonucleotide (FIG. 8A) or 60 pMof chloroquine and / or 20 mM of calcium chloride (FIG. 8B) in comparison to in combination with lipofectamine.FIG. 9A shows the amount of luminescence measured in primary adipocytes for circular polyribonucleotides encoding a luciferase polypeptide complexed with an oligomer conjugated to a cholesterol by way of a linker and / or an oligomer conjugated to a tocopherol by way of a linker in the presence or absence of calcium in comparison to a circular polyribonucleotide in the presence of lipofectamine.FIG. 9B shows the amount of flux measured for circular polyribonucleotides encoding a luciferase polypeptide complexed with: (a) an oligomer conjugated to a cholesterol by way of a linker and an oligomer conjugated to a tocopherol, or (b) an oligomer conjugated to an aptamer by way of a linker 6 hours, 24 hours, and 48 hours after subcutaneous administration to mice in comparison to a circular polyribonucleotide administered with lipid nanoparticles (LNP).FIG. 10 shows a schematic of circular polyribonucleotide complexed with a biotinylated oligomer bound to avidin having three additional biotin binding sites which may bind one or more biotinylated targeting moieties such as biotinylated lipids, biotinylated sugars, biotinylated peptides, or biotinylated antibodies.FIG. 11 A shows the amount of luminescence measured in HEK293T cells transfected with circular polyribonucleotides encoding a luciferase polypeptide either alone or complexed with an oligomer conjugated to cholesterol by way of a linker in various concentrations of calcium.FIG. 11 B shows the amount of flux measured in mice 72 hours after they were administered circular polyribonucleotides encoding a luciferase polypeptide either alone or complexed with an oligomer conjugated to cholesterol by way of a linker in various concentrations of calcium in comparison to a circular polyribonucleotide administered with an LNP.FIG. 12A shows the amount of luminescence measured in primary mouse hepatocytes transfected with circular polyribonucleotides encoding a luciferase polypeptide either alone or complexed with an oligomer conjugated to tocopherol by way of a linker and an oligomer conjugated to GalNAc by way of a linker in various concentrations of calcium, chloroquine, and / or ribonuclease inhibitor in comparison to a circular polyribonucleotide in lipofectamine.FIG. 12B shows the amount of flux measured in mice 5 hours after they were administered circular polyribonucleotides encoding a luciferase polypeptide either alone or complexed with an oligomer conjugated to cholesterol by way of a linker in various concentrations of calcium and / or chloroquine.FIG. 13 show the polypeptide expression resulting from administering a circular polyribonucleotide encoding a SARS-CoV-2 RNA binding protein (RBD) that is complexed either to (a) an oligomer conjugated to cholesterol by way of a linker, or (b) a biotinylated oligomer bound to an avidin bound to biotinylated mannose in the presence or absence of chloroquine.FIG. 14A and FIG. 14B shows the amount of flux measured in mice 4-5 hours, 24 hours, and 72 hours after they were intramuscularly administered circular polyribonucleotides encoding a luciferase polypeptide either alone or complexed with: (a) an oligomer conjugated to a biotinylated avidin conjugated to biotinylated mannose by way of a linker, or (b) an oligomer conjugated to a tocopherol by way of a linker and an oligomer conjugated to a cholesterol by way of a linker in comparison to a circular polyribonucleotide administered with an LNP and visualized by the dorsal (FIG. 14A) or ventral view (FIG. 14B).FIG. 15 shows the amount of flux measured in mice over a period of 30 days after they were intradermally administered circular polyribonucleotides encoding a luciferase polypeptide either alone or complexed with an oligomer conjugated to cholesterol by way of a linker or an oligomer, wherein the complex is mixed with chloroquine, calcium, albumin, and ribonuclease inhibitor, in comparison to a circular polyribonucleotide administered with an LNP and visualized by the dorsal view.FIG. 16 shows the amount of flux measured in mice 6 hours, 24 hours, or 48 hours after they were subcutaneously administered circular polyribonucleotides encoding a luciferase polypeptide either alone or complexed with: (a) an oligomer conjugated to cholesterol by way of a linker and an oligomer and an oligomer conjugated to tocopherol by way of a linker, (b) a oligomer conjugated to an aptamer by way of a linker, and (c) within an LNP and visualized by the dorsal view.FIG. 17A and FIG. 17B show the percentage of cells that internalized (FIG. 17A) and the mean uptake of cells (FIG. 17B) of the circular polyribonucleotides complexed to: (a) a biotinylated oligomer bound to an avidin bound to an antibody at various concentrations; (b) two biotinylated oligomers each bound to an avidin bound to an antibody and a biotinylated oligomer bound to an avidin conjugated to a mixture of two different antibodies; (c) two biotinylated oligomers each bound to an avidin bound to an antibody and a biotinylated oligomer bound to an avidin conjugated to a mixture of two different aptamers; (d) two biotinylated oligomers each bound to an avidin bound to an antibody and a biotinylated oligomer bound to an avidin conjugated to a mixture of an antibody and phosphatidylserine; or (e) a biotinylated oligomer bound to an avidin conjugated to a phosphatidylserine.FIG. 18 shows the number copies of the circular polyribonucleotide measured to be internalized by Raw264.7 macrophages, wherein the circular polyribonucleotide is complexed with: (a) two biotinylated oligomers each of which are bound to an avidin which is bound to a mixture of antibodies, aptamers, phosphatidylserine, and / or mannose; or (b) an oligomer conjugated to tocopherol by way of a linker and an oligomer conjugated to cholesterol by way of a linker in the presence or absence of calcium. FIG. 18 demonstrates that the various complexed circular polyribonucleotides were localized inside the cells.FIG. 19 shows the amount of luminescence measured in Raw264.7 macrophages having been transfected with a circular polyribonucleotide complexed two biotinylated oligomers each of which are bound to an avidin which is bound to one or more targeting moieties including: an aptamer, antibody, mannose, phosphatidylserine or a mixture thereof in the presence or absence of chloroquine.FIG. 20 shows the amount of luminescence measured for circular polyribonucleotides complexed with either two biotinylated oligomers in comparison to a circular polyribonucleotide complexed with to oligomers each of which independently were bound to an avidin which was bound to biotinylated antibodies.FIG. 21 shows the amount of luminescence measured in HeLa cells after having been transfected with a circular polyribonucleotide encoding a luciferase polypeptide complexed with two biotinylated oligomers each bound to avidin which was bound to Trf antibodies, wherein the complex was administered in the presence or absence of calcium and / or excess transferrin.FIG. 22 shows the amount of luminescence measured from circular polyribonucleotides encoding a luciferase polypeptide bound to a GalNAc targeting moiety in comparison to a circular polyribonucleotide without a targeting moiety. The GalNAc targeting moiety was conjugated by way of alinker at the 5’ end (FC and FC) or 3’ end (FA and FB) an oligomer annealed to the ORF of the circular polyribonucleotide. The linker was either a TEG linker (FA, FB, FC, and FD) or PEG24 linker (FE24).FIG. 23 is a schematic of an exemplary circular polyribonucleotide complexed with X(L-B), where X is a moiety that binds specifically to a region of the circular polyribonucleotide and includes a photoreactive crosslinking agent, L is a linker, and B is a targeting moiety.FIG. 24 is an HPLC chromatogram showing a linear, complementary oligomer (oligomimic) and a binding moiety that includes a 23-mer ribonucleotide, a 3-cyanovinylcarbazole nucleoside (CNVK) photoreactive crosslinking agent, a linker, and a biotin targeting moiety, wherein the linear complementary oligomer and the binding moiety were bound by annealing or by annealing and irradiation.FIG. 25A and 25B are graphs showing the amount of luminescence measured in HEK293 cells transfected with circular polyribonucleotides encoding a luciferase polypeptide complexed with a dimeric fluorescent TAT (dfTAT) peptide (eRNA) complexed by way of annealing then irradiation for 0, 1 , 5, or 30 minutes. The circular polyribonucleotide was complexed with an oligomer bound to an E1 binding region (Chol-E1-cnvK) of the circular polyribonucleotide or an oligomer bound to an E1 / E2 binding region (Chol- E2 / E1-cnvK) of the circular polyribonucleotide. The results are compared to no circular polyribonucleotides, the circular polyribonucleotides without a binding moiety, the circular polyribonucleotides without a binding moiety, and transfected with lipofectamine MessengerMax (lipo). J=Chol J including a cholesterol targeting moiety. FIG. 25B shows the same data as FIG. 25A but is rearranged to emphasize the significant expression of the complex including Chol-E1-cnvK as a binding moiety after irradiation for 30 minutes.FIG. 26A and 26B are graphs showing the amount of luminescence measured in HEK cells transfected with circular polyribonucleotides encoding a luciferase polypeptide (eRNA) complexed by way of annealing and irradiation for 0 or 30 minutes. The circular polyribonucleotide was complexed with an oligomer including one internally located photoreactive crosslinking agent (PS1 D and CHOL-E1_CK) or an oligomer including two internally located photoreactive crosslinking agents (PS2E). J=Chol J including a cholesterol targeting moiety; Q=Chol J including a tocopherol binding moiety. The results are compared to circular polyribonucleotides without a binding moiety. FIG. 26Bshows the same data from FIG. 26A but is rearranged to emphasize complexes including oligomers with significant expression after irradiation for 30 minutes.Detailed DescriptionThis disclosure provides compositions, pharmaceutical preparations, and uses of circular polyribonucleotides complexed with one or more targeting moieties. The circular polyribonucleotide complexes described herein improve the efficiency of delivery to a cell or a subject, as compared to the same circular polyribonucleotide alone.This disclosure provides compositions, pharmaceutical preparations, and uses of circular polyribonucleotides complexed by one or more photoreactive crosslinking agents with one or more targeting moieties. Also featured are covalent complexes produced with photoreactive crosslinking agents. The circular polyribonucleotide complexes described herein improve the efficiency of delivery to a cell or a subject, as compared to the same circular polyribonucleotide alone. In particular, the photoreactive crosslinking agent is able to form a covalent adduct upon irradiation between the targeting moiety and the circular polyribonucleotide, providing increase stability of the targeting complex to moreefficiently deliver the complex to a desired intracellular or extracellular location. The targeting moiety may be, for example, a small molecule, a polypeptide, a carbohydrate, a lipid, a nucleic acid (e.g., an aptamer), or a combination thereof.In some embodiments, the circular polyribonucleotide encodes a therapeutic agent (e.g., a therapeutic polypeptide), the complex improves therapeutic efficacy. In some embodiments, the circular polyribonucleotide encodes a polypeptide, the complex improves translation efficiency.Complexes and compositions described herein may be complexed with or encapsulated by a carrier (e.g., a cell, a vesicle, a membrane-based carrier, a lipid nanoparticle (LNP), a polymer nanoparticle, a viral particle, or a microbubble). Complexes and compositions described herein may have no carrier. Complexes and compositions described herein may be formulated as a pharmaceutical composition, e.g., for therapeutic use. Complexes and compositions described herein may be used to treat a disease, disorder, or condition, as described herein.The disclosure provides a complex including a circular polyribonucleotide, a moiety that binds specifically to a region of the circular polyribonucleotide and contains one or more photoactivatable crosslinking agents, a linker, and targeting moiety. For example, the circular polyribonucleotide may be complexed with a molecule of Xn(L-B)z, where each X is independently a moiety that binds specifically to a region of the circular polyribonucleotide and contains one or more photoactivatable crosslinking agents, each L is independently a linker, each B is independently a targeting moiety, n is an integer, e.g., from 1 to 20, and z is an integer, e.g., from 1 to 5 (see, e.g., FIG. 23). The moiety that binds the circular polyribonucleotide may be, for example, an oligonucleotide, a polypeptide, or a small molecule.This disclosure also provides compositions of and methods for forming a covalent complex including A and Xn(L-B)z, where is a circular polyribonucleotide, each X is independently a moiety that binds specifically and is covalently attached to a region of A, each L is independently a linker, each B is independently a targeting moiety, n is an integer, e.g., from 1 to 20, and z is an integer, e.g., from 1 to 5. The moiety that binds the circular polyribonucleotide may be, for example, an oligonucleotide, a polypeptide, or a small molecule.Targeting MoietiesThe disclosure provides a complex including a circular polyribonucleotide, a moiety that binds specifically to a region of the circular polyribonucleotide, a linker, and targeting moiety. In some embodiments, the disclosure provides a circular polyribonucleotide including from 1 to 20 moieties (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, and 20) that binds specifically to a region of the circular polyribonucleotide conjugated to a linker and a targeting moiety. For example, the circular polyribonucleotide may be complexed with Xn(L-B)z, wherein A is a circular polyribonucleotide, each X is independently a moiety that binds specifically to a region of A, each L is independently a linker, each B is independently a targeting moiety, wherein n is an integer from 1 to 20, and wherein z is an integer from 1 to 5; for example, as shown in FIG. 1 . In some embodiments, n is an integer from 1 to 5 (e.g., 1 , 2, 3, 4, and 5).In some embodiments, the disclosure provides a complex including a circular polyribonucleotide, one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) moieties that each binds specifically to a region of the circular polyribonucleotide and includes one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more)photoreactive crosslinking agents or covalent attachments, a linker, and one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) targeting moieties.In some embodiments, the disclosure provides a complex including a circular polyribonucleotide, a moiety that binds specifically to a region of the circular polyribonucleotide, a linker, and two or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) targeting moieties. In some embodiments, the target moieties are the same targeting moiety. In some embodiments, the targeting moieties are different from one another. Examples of combinations of targeting moieties are described in Table 1. The targeting moiety may be a small molecule, a polypeptide, a carbohydrate, a lipid, a nucleic acid (e.g., an aptamer), or a combination thereof. In some embodiments, the targeting moiety is not an aptamer. In some embodiments, the targeting moiety is biotinylated.Table 1. Combinations of Targeting MoietiesThe circular polyribonucleotide may be bound to two targeting moieties (e.g., Xn(L-B)zincludes B1-L-X-L-B2wherein each of B1and B2is an independently selected targeting moiety selected from any targeting moiety described herein, and wherein z is 2). For example, that circular polyribonucleotide may be bound to a GalNAc targeting moiety and a tocopherol targeting moiety. In some embodiments, the two targeting moieties are a GalNAc targeting moiety and a cholesterol targeting moiety. In some embodiments, both targeting moieties are lipid targeting moieties. For example, the two lipid targeting moieties may be a tocopherol and a cholesterol targeting moiety.The circular polyribonucleotide may be bound to 1 , 2, 3, 4, or 5 targeting moieties (e.g., Xn(L-B)z, wherein z is 1 , 2, 3, 4, or 5, and Bzis up to 5 independently selected targeting moieties selected from any targeting moiety described herein). In some embodiments, all targeting moieties are different. For example, the circular polyribonucleotide may be bound to a GalNAc targeting moiety, a tocopherol targeting moiety, a urea targeting moiety, a melittin targeting moiety, and an aptamer targeting moiety. In some embodiments, all targeting moieties are the same class of moiety, but differ within that class. For example, the circular polyribonucleotide may be bound to four lipid targeting moieties, wherein the lipid targeting moieties are cholesterol, tocopherol, vitamin A, and phosphocholine. In some embodiments, alltargeting moieties are the same. For example, the circular polyribonucleotide may be bound to 1 , 2, 3, 4, or 5 GalNAc targeting moieties. In some embodiments, 2, 3, or 4 targeting moieties are the same and 1 targeting moiety is different. In some embodiments, 2 or 3 targeting moieties are the same and 1 or 2 are different. In some embodiments, 2 targeting moieties are the same and 1 , 2, or 3 are different. For example, the circular polyribonucleotide may be bound to two tocopherol targeting moieties, one cholesterol targeting moiety, and one aptamer targeting moiety. In another example, the circular polyribonucleotide may be bound to two tocopherol targeting moieties and two cholesterol moieties. In some embodiments, 2 sets of 2 targeting moieties are the same and one is different. For example, a circular polyribonucleotide may be bound to two GalNAc targeting moieties, two cellulose targeting moieties, and one Transportan targeting moiety.In some embodiments, the targeting moiety targets (e.g., binds to or delivers the circular polynucleotide preferentially to) a specific cell type; for example, the polypeptide targeting moiety may preferentially target hepatic cells, muscle cells (e.g., skeletal muscle cell), blood cells, bone cells, fat cells, skin cells, nerve cells, endothelial cells, stem cells, sex cells, pancreatic cells, or cancer cells. In particular embodiments, the polypeptides target cancer cells (e.g., tumor cells). In some embodiments, the polypeptide targeting moiety targets cells of a specific organ; for example, the polypeptide targeting moiety may preferentially target cells in the heart, lungs, liver, or kidneys.Lipid Targeting MoietiesIn some embodiments, the targeting moiety complexed to the circular polyribonucleotide is a lipid. Lipid moieties include organic compounds, most preferably organic biomolecules, that are selectively soluble in nonpolar solvents over water. Lipid moieties specifically contemplated by the present invention include, for example, fatty acids, steroids or sterols, glycerides (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids (e.g., phosphatidylcholines), fat-soluble vitamins (e.g., vitamins A, D, E, and K), cationic lipids, ionizable lipids, or zwitterionic lipids.In some embodiments, the lipid moiety is a fatty acid. A fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. The fatty acid may be naturally occurring, a modified variant of a naturally occurring fatty acid, or a synthetic (e.g., non-naturally occurring fatty acid). Fatty acids are known to those of skill in the art. In some embodiments the fatty acid is a saturated fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid includes a branched or unbranched chain including from 4 to 40 main-chain carbon atoms (e.g., from 4 to 28 main-chain carbon atoms, from 4 to 15 main-chain carbon atoms, from 10 to 30 main-chain carbon atoms, or from 15 to 40 main-chain carbon atoms). In some embodiments, the fatty acid includes squalene, stearic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, lauric acid, docosahexaenoic acid (DHA), docosanoic acid (DCA), eicosapentaenoic acid (EPA), octadecanoic acid, myristic acid, anadamide, a-tocopherol, a-tocopherol succinate, or a retinoic acid (e.g., all-trans-retinoic acid), or an analog or metabolite thereof. In some embodiments, the fatty acid includes one, two, three, four, or five lipid chains (e.g., aliphatic lipids selected from above).In some embodiments, the lipid moiety is a steroid or a sterol. Steroid and sterols are known to those of skill in the art. In general, a steroid is an organic compound with four rings in a fused ring molecular configuration, in particular, a having a core cyclopentanoperhydrophenanthrene ring system. A sterol is any steroid-based alcohol. Steroids and sterols may be naturally occurring or synthetic. In someembodiments, the steroid or sterol is selected from cholesterol, ursodeoxycholic acid, lithocholic acid, or an analog or metabolite thereof.In some embodiments, the lipid moiety is a fat-soluble vitamin. In some embodiments, the fat- soluble vitamin is selected from vitamin A, vitamin D, vitamin E, vitamin K, or an analog or metabolite thereof.In some embodiments, the lipid moiety is a phospholipid. Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group, and one or more (e.g., two) hydrophobic "tails" derived from fatty acids, often joined by an alcohol residue. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine, or serine. In some embodiments, the phospholipid is a phosphatidylcholine (e.g., phospholipids that incorporate choline as a headgroup). In some embodiments, the phosphatidylcholine is selected from phosphocholine (PC), PC- docosahexaenoic acid (PC-DHA), PC-docosanoic acid (PC-DCA), PC-eicosapentaenoic acid (PC-EPA), PC-lithocholic acid (PC-LA), PC-retinoic acid (PC-RA), or PC-a-tocopherol succinate (PC-TS).Any of the above-described lipid moieties may be chemically-modified (e.g., derivatized or conjugate to a linker) to allow for conjugation to a nucleic acid (e.g., an oligonucleotide or a circular polyribonucleotide). Any of the above-described lipid moieties may also be biotinylated to facilitate binding to a biotin-binding protein (e.g., avidin, streptavidin, NeutrAvidin).Small Molecule Targeting MoietiesThe disclosure provides small molecule targeting moieties which may form a complex with a circular polyribonucleotide. Small molecule targeting moiety have an average molecular weight less than 1 kDa, corresponding to a Stokes-Einstein radius of 1 nm. For example, the small molecule may have a molecular weight of from about 300 to about 700 Da (e.g., about 325 Da, about 350 Da, about 375 Da, about 400 Da, about 425 Da, about 450 Da, about 475 Da, about 500 Da, about 525 Da, about 550 Da, about 575 Da, about 600 Da, about 625 Da, about 650 Da, or about 675 Da). In some embodiments, the small molecule may have a molecular weight of from 500 Da to 1000 Da (e.g., from about 500 Da to 900 Da, about 500 Da to 800 Da, 500 Da to 700 Da, 500 Da to 600 Da, 600 Da to 1000 Da, 700 Da to 1000 Da, 800 Da to 1000 Da, or 900 Da to 1000 Da).Small molecule targeting moieties, upon reaching the target tissue, must cross the plasma membrane to reach the cytosol or nucleus of the cell. The plasma membrane is relatively permeable to hydrophobic small molecules. However, the transport of macromolecules requires an active uptake mechanism, which requires the small molecule have efficient interactions with the plasma membrane and subsequent endocytosis processes, such as phagocytic-, clathrin-, and caveolae-mediated endocytosis. The small molecule binding targeting moieties specifically bind to a protein of a cell and the protein mediates internalization of the circular polyribonucleotide bound to the targeting small molecule moiety into the cell upon binding to the targeting small molecule moiety.In some embodiments, the small molecule targeting moiety is folic acid. Folic acid may enable efficient intracellular delivery of the circular polyribonucleotide, following folic acid receptor mediated endocytosis. In some embodiments, the small molecule targeting molecule is urea. Urea may be internalized into the cell using clathrin-mediated endocytosis to deliver the attached circular polyribonucleotide. In some embodiments, the small molecule may be glutamate urea or 2-[3-(1 ,3- dicarboxypropyl)-ureido] pentanedioic acid. Urea may be used as a small molecule targeting moiety totarget the prostate specific membrane antigen (PSMAIn some embodiments, the small molecule is ursodexoycholic acid. In some embodiments, the small molecule is lithocholic acid. In some embodiments, glycyrrhetinic acid derivatives may be the small molecule targeting moiety. Glycyrrhetinic acid derivatives may be used for hepatocellular applications due to presence of glycyrrhetinic acid receptors. In some embodiments, a sulfonamide may be used as the small molecule targeting moiety. Sulfonamide derivatives may be used to target tumors expressing carbonic anhydrase IX. In some embodiments, a benzamide may be used as the small molecule targeting moiety. Benzamides, such as anisamide, may be used to specifically target sigma-1 receptors. In some embodiments, phenyl boronic acid may be used as the small molecule targeting moiety. Phenyl boronic acid may be used to target components of sialic acid. In some embodiments, hyaluronic acid may be used as the small molecule targeting moiety. Hyaluronic acid has been shown to have affinity toward CD44 receptors. In some embodiments, bisphosphonate may be used as the small molecule targeting moiety. Bisphosphonates may be used to effectively target bone. In some embodiments, biotin may be used as the small molecule targeting moiety. Biotin-mediated drug delivery may be used for tumor targeting applications by way of the biotin receptor. In some embodiments, biotin may be conjugated to any of the above-described small molecules to facilitate binding to a biotin-binding protein (e.g., avidin, streptavidin, NeutrAvidin).Carbohydrate Targeting MoietiesThe disclosure provides carbohydrate targeting moieties which may form a complex with a circular polyribonucleotide. The carbohydrate targeting moiety may, for example, include a saccharide, disaccharide, or polysaccharide. In some embodiments, the carbohydrate includes mannose, galactose, or glucose. In some embodiments, a carbohydrate moiety described herein includes one or more monosaccharide moieties. In some embodiments, the one or more monosaccharide moieties includes at least 3 carbon atoms (e.g., arranged in a linear, branched, or cyclic structure) and an oxygen, nitrogen, or sulfur atom, or a fragment or variant of a monosaccharide moiety including at least 3 carbon atoms (e.g., arranged in a linear, branched, or cyclic structure) and an oxygen, nitrogen, or sulfur atom. Each monosaccharide moiety or fragment or variant thereof may be a tetrose, pentose, hexose, or heptose . Each monosaccharide moiety or fragment or variant thereof may exist as an aldose, ketose, sugar alcohol, and, where appropriate, in the L or D form. Exemplary monosaccharide moieties may be amino sugars, N-acetylamino sugars, imino sugars, deoxysugars, or sugar acids. Carbohydrates may include individual monosaccharide moieties, or may further include a disaccharide, oligosaccharide (e.g., a trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, heptasaccharide, octasaccharide), a polysaccharide, or combinations thereof. Exemplary carbohydrates include ribose, arabinose, lyxose, xylose, deoxyribose, ribulose, xylulose, glucose, galactose, mannose, gulose, idose, talose, allose, altrose, psicose, fructose, sorbose, tagatose, rhamnose, pneumose, quinovose, fucose, mannuheptulose, sedoheptulose, galactosamine, mannosamine, glucosamine, N-acetylglucosamine, N- acetylgalactosamine, N-acetylmannosamine, glucuronic acid, galacturonic acid, mannuronic acid, guluronic acid, iduronic acid, tagaturonic acid, frucuronic acid, galactosaminuronic acid, mannosaminuronic acid, glucosaminuronic acid, N-acetylglucosaminuronic acid, N- acetylgalactosaminuronic acid, N-acetylmannosaminuronic acid, maltose, lactose, sucrose, trehalose, gentiobiose, cellobiose, chitobiose, kojibiose, nigerose, sophorose, trehalulose, isomaltose, xylobiose, starch, cellulose, chitin, and dextran.The carbohydrate moiety may include one or more monosaccharide moieties linked by a glycosidic bond. In some embodiments, the glycosidic bond includes a 1 ^2 glycosidic bond, a 1^3 glycosidic bond, a 1^4 glycosidic bond, or a 1^6 glycosidic bond. In some embodiments, each glycosidic bonds may be present in the alpha or beta configuration. In an embodiment, the one or more monosaccharide moieties are linked directly by a glycosidic bond or are separated by a linker.The term “carbohydrate” as used herein refers to compound including one or more monosaccharide moieties including at least 3 carbon atoms (e.g., arranged in a linear, branched, or cyclic structure) and an oxygen, nitrogen, or sulfur atom, or a fragment or variant of a monosaccharide moiety including at least 3 carbon atoms (e.g., arranged in a linear, branched, or cyclic structure) and an oxygen, nitrogen, or sulfur atom. Each monosaccharide moiety or fragment or variant thereof may be a tetrose, pentose, hexose, or heptose. Each monosaccharide moiety or fragment or variant thereof may exist as an aldose, ketose, sugar alcohol, and, where appropriate, in the L or D form. Exemplary monosaccharide moieties may be amino sugars, N-acetylamino sugars, imino sugars, deoxysugars, or sugar acids. Carbohydrates may include individual monosaccharide moieties, or may further include a disaccharide, oligosaccharide (e.g., a trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, heptasaccharide, octasaccharide), a polysaccharide, or combinations thereof. Exemplary carbohydrates include ribose, arabinose, lyxose, xylose, deoxyribose, ribulose, xylulose, glucose, galactose, mannose, gulose, idose, talose, allose, altrose, psicose, fructose, sorbose, tagatose, rhamnose, pneumose, quinovose, fucose, mannuheptulose, sedoheptulose, galactosamine, mannosamine, glucosamine, N- acetylglucosamine, N-acetylgalactosamine, N-acetylmannosamine, glucuronic acid, galacturonic acid, mannuronic acid, guluronic acid, iduronic acid, tagaturonic acid, frucuronic acid, galactosaminuronic acid, mannosaminuronic acid, glucosaminuronic acid, N-acetylglucosaminuronic acid, N- acetylgalactosaminuronic acid, N-acetylmannosaminuronic acid, maltose, lactose, sucrose, trehalose, gentiobiose, cellobiose, chitobiose, kojibiose, nigerose, sophorose, trehalulose, isomaltose, xylobiose, starch, cellulose, chitin, and dextran.The carbohydrate may include one or more monosaccharide moieties linked by a glycosidic bond. In some embodiments, the glycosidic bond includes a 1->2 glycosidic bond, a 1->3 glycosidic bond, a 1->4 glycosidic bond, or a 1->6 glycosidic bond. In some embodiments, each glycosidic bonds may be present in the alpha or beta configuration. In an embodiment, the one or more monosaccharide moieties are linked directly by a glycosidic bond or are separated by a linker.In some embodiments, the present disclosure features a circular polyribonucleotide complexed with a carbohydrate targeting moiety, wherein the carbohydrate targeting moiety includes an asialoglycoprotein receptor (ASGPR) binding moiety. The ASGPR is a C-type lectin primarily expressed on the sinusoidal surface of hepatocytes, and includes a major (48 kDa, ASGPR-1) and a minor (40 kDa, ASGPR-2) subunit. The ASGPR is involved in the binding, internalization, and subsequent clearance of glycoproteins containing an N-terminal galactose (Gal) or N-terminal N-acetylgalactosamine (GalNAc) residues from circulation, such as antibodies. ASGPRs have also been shown to be involved in the clearance of low-density lipoprotein, fibronection, and certain immune cells, and may be utilized by certain viruses for hepatocyte entry (see, e.g., Yang J., et al (2006) J Viral Hepat 13:158-165 and Guy, CS et al (2011) Nat Rev Immunol 8:874-887).In some embodiments, the carbohydrate targeting moiety is mannose. For example, carbohydrate targeting moiety may be a-mannose or high-mannose. In some embodiments, thecarbohydrate targeting moiety includes a mannose 6-phosphate (M6P) or analog thereof. In an embodiment, the carbohydrate targeting moiety include a plurality of M6P moieties (e.g., M6Ps), e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or more M6P moieties. In an embodiment, the carbohydrate targeting moiety includes from 2 to 20 M6P moieties (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 M6P moieties). In an embodiment, the carbohydrate targeting moiety includes from 2 to 10 M6P moieties (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 M6P moieties). In an embodiment, the carbohydrate targeting moiety includes from 2 to 5 M6P moieties (e.g., 2, 3, 4, or 5 M6P moieties).In some embodiments, the carbohydrate targeting moiety includes a galactose (Gal), galactosamine (GalNH2), or an N-acetylgalactosamine (GalNAc) moiety, for example, a Gal, GalNH2, or GalNAc, or an analog thereof. In an embodiment, the carbohydrate targeting moiety includes a GalNAc moiety (e.g., GalNAc). In an embodiment, the carbohydrate targeting moiety includes a plurality of GalNAc moieties (e.g., GalNAcs), e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or more GalNAc moieties (e.g., GalNAcs). In an embodiment, the carbohydrate targeting moiety includes from 2 to 20 GalNAcs moieties (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 GalNAc moieties). In an embodiment, the carbohydrate targeting moiety includes from 2 to 10 GalNAc moieties (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 GalNAc moieties). In an embodiment, the carbohydrate targeting moiety includes from 2 to 5 GalNAc moieties (e.g., 2, 3, 4, or 5 GalNAc moieties). In an embodiment, the carbohydrate targeting moiety includes 2 GalNAc moieties. In an embodiment, the carbohydrate targeting moiety includes 3 GalNAc moieties. In an embodiment, the carbohydrate targeting moiety includes 4 GalNAc moieties. In an embodiment, the carbohydrate targeting moieties includes 5 GalNAc moieties. In some embodiments, the carbohydrate targeting moiety includes a mono-, di-, tri-, or tetra-GalNAcIn some embodiments, the GalNAc moiety includes a structure of Formula (I):salt thereof, wherein X is O, N(R7), or S; each of R1, R3, R4, and R5are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, C(O)-alkyl, C(O)-alkenyl, C(O)-alkynyl, C(O)-heteroalkyl, C(O)-haloalkyl, C(O)-aryl, C(O)- heteroaryl, C(O)-cycloalkyl, or C(O)-heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R8; R2ais hydrogen or alkyl; R2bis -C(O)alkyl (e.g., C(O)CH3); each of R6aand R6bis hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, halo, cyano, nitro, -ORA, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R9; R7is hydrogen, alkyl, or C(O)-alkyl; each of R8and R9is independently hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl; and RAis hydrogen, or alkyl, alkenyl, alkynyl, wherein the structure of Formula (I) may be connected to a linker at any position.In some embodiments, X is O. In some embodiments, each of R1, R3, R4, and R5are independently hydrogen or alkyl (e.g., CH3). In some embodiments, R2ais hydrogen. In someembodiments, R2bis C(O)CH3. In some embodiments, each of R6aand R6bis hydrogen. In some embodiments, the GalNAc moiety is connected to a linker at R2a. In some embodiments, the GalNAc moiety is connected to a linker at R2b. In some embodiments, the GalNAc moiety is connected to a linker or at R3. In some embodiments, the GalNAc moiety is connected to a linker at R4. In some embodiments, the GalNAc moiety is connected to a linker at R5. In some embodiments, the GalNAc moiety is connected to a linker at R6aor R6b. In some embodiments, the GalNAc moiety is connected to a linker at a plurality of positions, e.g., at least two of R1, R2a, R2b, R3, R4, R5, R6a, and R6b.In some embodiments, the GalNAc moiety is includes a structure of Formula (l-a)(|_a)or a sa|| thereof,wherein R2ais hydrogen or alkyl; R2bis -C(O)alkyl (e.g., C(O)CH3); each of R3, R4, and R5are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, C(O)-alkyl, C(O)-alkenyl, C(O)-alkynyl, C(O)- heteroalkyl, C(O)-haloalkyl, C(O)-aryl, C(O)-heteroaryl, C(O)-cycloalkyl, or C(O)-heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R8; and R8is hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl, wherein the represents a bond in any configuration, and represents an attachment point to a linker.In some embodiments, each of R3, R4, and R5are independently hydrogen or alkyl (e.g., CH3). In some embodiments, R2ais hydrogen. In some embodiments, R2bis C(O)CH3.In some embodiments, the carbohydrate targeting moiety includes a structure of Formula (II):(II), or a salt thereof, wherein each of R1, R2a, R2b, R3,R4, R5, R6a, and R6band subvariables thereof are as defined for Formula (I), L is a linker, and n is an integer from 1 to 100, wherein represents an attachment point to a branching point, additional linker.In some embodiments, X is O. In some embodiments, each of R1, R3, R4, and R5are independently hydrogen or alkyl (e.g., CH3). In some embodiments, R2ais hydrogen. In some embodiments, R2bis C(O)CH3. In some embodiments, each of R6aand R6bis hydrogen. In some embodiments, n is an integer from 1 to 50. In some embodiments, n is an integer from 1 to 25. In some embodiments, n is an integer from 1 to 10. In some embodiments, n is an integer from 1 to 5. In some embodiments, n is 1 , 2, 3, 4, or 5. In some embodiments, n is 1.In some embodiments, the carbohydrate targeting moiety includes a structure of Formula (ll-a):(I l-a) , or a salt thereof, wherein each ofR1, R2a, R2b, R3, R4, R5, R6a, and R6band subvariables thereof are as defined for Formula (I), each of L1and L2is independently a linker, each of m and n is independently an integer from 1 to 100, and M is a linker, wherein represents an attachment point to a branching point, additional linker.In some embodiments, X is O (e.g., X in each of A and B is O). In some embodiments, each of R1, R3, R4, and R5are independently hydrogen or alkyl (e.g., CH3) (e.g., R1, R3, R4, and R5in each of A and B is independently hydrogen or alkyl). In some embodiments, R2ais hydrogen (e.g., R2ain each of A and B is hydrogen). In some embodiments, R2bis C(O) CH3(e.g., R2bin each of A and B is C(O)CH3). In some embodiments, each of R6aand R6bis hydrogen (e.g., R6aand R6bin each of A and B is hydrogen). In some embodiments, each of m and n is independently an integer from 1 to 50. In some embodiments, each of m and n is independently an integer from 1 to 25. In some embodiments, each of m and n is independently an integer from 1 to 10. In some embodiments, each of m and n is independently an integer from 1 to 5. In some embodiments, each of m and n is independently 1 , 2, 3, 4, or 5. In some embodiments, each of m and n is independently 1.In an embodiment, each of L1and L2independently includes an alkylene, alkenylene, alkynylene, heteroalkylene, or haloalkylene group. In an embodiment, each of L1and L2independently includes an ester, amide, disulfide, ether, carbonate, aryl, heteroaryl, cycloalkyl, or heterocyclyl group. In an embodiment, each of L1and L2independently is cleavable or non-cleavable.In some embodiments, M includes an alkylene, alkenylene, alkynylene, heteroalkylene, or haloalkylene group. In an embodiment, M includes an ester, amide, disulfide, ether, carbonate, aryl, heteroaryl, cycloalkyl, or heterocyclyl group. In an embodiment, M is cleavable or non-cleavable.In some embodiments, the ASGPR moiety includes a structure of Formula (I l-b):(I l-b), or a salt thereof, wherein each of R1,R2a, R2b, R3, R4, R5, R6a, and R6band subvariables thereof are as defined for Formula (I), each of L1, L2, and L3is independently a linker, each of m, n, and o is independently an integer from 1 to 100, and M is a linker, wherein represents an attachment point to a branching point, additional linker.In some embodiments, X is O (e.g., X in each of A, B, and C is O). In some embodiments, each of R1, R3, R4, and R5are independently hydrogen or alkyl (e.g., CH3) (e.g., R1, R3, R4, and R5in each of A, B, and C is independently hydrogen or alkyl). In some embodiments, R2ais hydrogen (e.g., R2ain each of A, B, and C is hydrogen). In some embodiments, R2bis C(O)CH3(e.g., R2bin each of A, B, and C is C(O)CH3). In some embodiments, each of R6aand R6bis hydrogen (e.g., R6aand R6bin each of A, B, andC is hydrogen). In some embodiments, each of m, n, and 0 is independently an integer from 1 to 50. In some embodiments, each of m, n, and 0 is independently an integer from 1 to 25. In some embodiments, each of m, n, and 0 is independently an integer from 1 to 10. In some embodiments, each of m, n, and 0 is independently an integer from 1 to 5. In some embodiments, each of m, n, and 0 is independently 1 , 2, 3, 4, or 5. In some embodiments, each of m, n, and 0 is independently 1 .In an embodiment, each of L1, L2, and L3independently includes an alkylene, alkenylene, alkynylene, heteroalkylene, or haloalkylene group. In an embodiment, each of L1, L2, and L3independently includes an ester, amide, disulfide, ether, carbonate, aryl, heteroaryl, cycloalkyl, or heterocyclyl group. In an embodiment, each of L1, L2, and L3independently is cleavable or non-cleavable.In some embodiments, M includes an alkylene, alkenylene, alkynylene, heteroalkylene, or haloalkylene group. In an embodiment, M includes an ester, amide, disulfide, ether, carbonate, aryl, heteroaryl, cycloalkyl, or heterocyclyl group. In an embodiment, M is cleavable or non-cleavable.In some embodiments, the carbohydrate targeting moiety includes a structure of Formula (I l-c):(I l-c) , or a salt thereof, wherein each of R2a, R2b, R3, R4,R5, and subvariables thereof are as defined for Formula (I), each of L1, L2, and L3is independently a linker, and M is a linker, whereinrepresents an attachment point to a branching point, additional linker.In some embodiments, each of R3, R4, and R5are independently hydrogen or alkyl (e.g., CH3). In some embodiments, R2ais hydrogen. In some embodiments, R2bis C(O)CH3.In an embodiment, each of L1, L2, and L3independently includes an alkylene, alkenylene, alkynylene, heteroalkylene, or haloalkylene group. In an embodiment, each of L1, L2, and L3independently includes an ester, amide, disulfide, ether, carbonate, aryl, heteroaryl, cycloalkyl, or heterocyclyl group. In an embodiment, each of L1, L2, and L3independently is cleavable or non-cleavable.In some embodiments, M includes an alkylene, alkenylene, alkynylene, heteroalkylene, or haloalkylene group. In an embodiment, M includes an ester, amide, disulfide, ether, carbonate, aryl, heteroaryl, cycloalkyl, or heterocyclyl group. In an embodiment, M is cleavable or non-cleavable.In some embodiments, the carbohydrate targeting moiety includes a compound selected from:In some embodiments, the carbohydrate targeting moiety includes a linker including a cyclic moiety, such as a pyrroline ring. In an embodiment, the carbohydrate targeting moiety includes a structure of Formula (CH):Formula (CII), or a salt thereof, wherein E is absent or C(O), C(O)O, C(O)NH, C(S), C(S)NH, SO, SO2, or SO2NH; R11, R12, R13, R14, R15, R16, R17, and R18are each independently for each occurrence H, — CH2ORa, or ORb; Raand Rbare each independently for each occurrence hydrogen, a hydroxyl protecting group, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted alkenyl, optionallysubstituted heteroaryl, polyethyleneglycol (PEG), a phosphate, a diphosphate, a triphosphate, a phosphonate, a phosphonothioate, a phosphonodithioate, a phosphorothioate, a phosphorothiolate, a phosphorodithioate, a phosphorothiolothionate, a phosphodiester, a phosphotriester, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, — P(Z1)(Z2) — O- nucleoside, — P(Z1)(Z2) — O-oligonucleotide, — P(Z1)(O-linker-RL) — O-nucleoside, or — P(Z1)(O-linker-RL) — O-oligonucleotide; R30is independently for each occurrence -linker-RLor R31; RLis hydrogen or a ligand; R31is — C(O)CH(N(R32)2)(CH2)hN(R32)2; R32is independently for each occurrence H, — RL, -linker- RL or R31; Z1is independently for each occurrence O or S; Z2is independently for each occurrence O, S, N(alkyl) or optionally substituted alkyl; and h is independently for each occurrence 1 -20. In some embodiments, the compound of Formula (Cll) is selected from:In some embodiments, the carbohydrate targeting moiety is a compound or substructure disclosed in U.S. Patent No. 8,106,022, which is incorporated herein by reference in its entirety. In other embodiments, the carbohydrate targeting moiety is selected from:wherein one ofX or Y is a branching point or a linker, and the other of X and Y is hydrogen.In an embodiment, the ASGPR moiety includes a structure of Formula (Xll-a):. In an embodiment, the carbohydrate targeting moiety is a compound or substructure disclosed in Nucleic Acids (2016) 5:e317 or WO2015 / 042447, each of which is incorporated herein by reference in its entirety.In some embodiments, the carbohydrate targeting moiety includes a structure of Formula (V-a):wherein n is an integer from 1 to 20.In some embodiments, the compound of Formula (V-a) is selected from:(V-a-iii), wherein Z is an oligomeric compound, e.g., a linker.In another embodiment, the carbohydrate binding moiety includes a structure of Formula (V-b):wherein A is O or S, A’ is O, S, orNH, and Z is an oligomeric compound, e.g., a linker.In some embodiments, the carbohydrate targeting moiety includesIn some embodiments, the carbohydrate targeting moiety is selected from:(V-c-i),(V-e-i).In an embodiment, the carbohydrate targeting moiety is a compound or substructure disclosed in WO 2017 / 156012, which is incorporated herein by reference in its entirety. In some embodiments, a hydroxyl group within a carbohydrate targeting moiety is protected, for example, with an acetyl or acetonide moiety. In some embodiments, a hydroxyl group within a carbohydrate targeting moiety is protected with an acetyl group. In some embodiments, a hydroxyl group within an ASGPR moiety is protected with acetonide group. For example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, or more hydroxyl groups within a carbohydrate targeting moiety may be protected, e.g., with an acetyl group or an acetonide group. In some embodiments, all of the hydroxyl groups within a carbohydrate targeting moiety are protected.In some embodiments, the carbohydrate targeting moiety includes an additional active agent, such as a ligand (e.g., a steroid). The ligand may be covalently or non-covalently associated with the carbohydrate targeting moiety. For example, the ligand may be covalently bound to a carbohydrate, linker, or a branching point within the carbohydrate targeting moiety. In some embodiments, the carbohydrate targeting moiety includeswherein one of X or Y is a branching point or linker, and the other of X and Y is hydrogen.Additional exemplary carbohydrate targeting moieties are described in further detail in U.S.Patent Nos. 8,828,956; 9,867,882; 10,450,568; and 10,808,246, each of which are incorporated herein by reference in its entirety.Any of the above-described carbohydrate targeting moieties may also be biotinylated to facilitate binding to a biotin-binding protein (e.g., avidin, streptavidin, NeutrAvidin).Polypeptide Targeting MoietiesThe disclosure provides polypeptide targeting moieties which may form a complex with a circular polyribonucleotide. The polypeptide targeting moieties may also be referred to as protein drug conjugates. The polypeptide targeting moieties specifically bind to a protein of a cell and the protein mediates internalization of the circular polyribonucleotide bound to the targeting polypeptide moiety into the cell upon binding to the targeting polypeptide moiety.The polypeptide targeting moiety may include all natural amino acids. In some embodiments, the polypeptide targeting moiety includes at least one unnatural amino acid reside; for example, the polypeptide targeting moiety may include 1 , 2, 3, 4, 5, 6, 8, 9, 10, or more unnatural amino acid residues. In some embodiments, the polypeptide targeting moiety may include all unnatural amino acid residues.In some embodiments, the polypeptide targeting moiety is a cell-penetrating peptide. A cell penetrating peptide may include from 2 to 100 amino acid residues (e.g., from 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 10 to 100, 20 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, and 90 to 100 amino acid residues). In some embodiments, the polypeptide targeting moiety includes from 2 to 50 amino acids (e.g., from 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 and 20, 2 to 15, 2 to 10, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, and 45 to 50 amino acid residues).Cell-penetrating peptides may be characterized as a synthetic cell-penetrating peptides, protein- derived cell-penetrating peptides, and chimeric cell-penetrating peptides. Furthermore, cell-penetrating peptides may be either linear or cyclic. Cell-penetrating peptides may also be categorized by physical properties and include cationic cell-penetrating peptides, amphipathic cell-penetrating peptides, or hydrophobic cell-penetrating peptides.The cell-penetrating peptide may be a one of the as described in Table 2. In some embodiments, the cell-penetrating peptide is melittin. In some embodiments, the cell-penetrating peptide is a TAT peptide. In some embodiments, the cell-penetrating peptide is Pep-1. In some embodiments, the cell- penetrating peptide is Transportan. In some embodiments, the cell-penetrating peptide is Penetratin. Further examples of cell-penetrating peptides may be found on the CPPsite 2.0 Database of Cell- Penetrating Peptides (webs.iiitd.edu.in / raghava / cppsite / information.php). This database contains >1500 cell-penetrating peptide sequences.Table 2. Exemplary Cell-Penetrating PeptidesIn some embodiments, cell-penetrating peptides may transport hydrophilic macromolecules to a cell through energy-independent pathways. Cell-penetrating peptides may enter the cell in a noninvasive way, as they usually do not disturb the structure of the plasma membranes and are considered safe and highly efficient. Some cell-penetrating peptides are reported to cross the cell membrane by an energy- dependent cellular process using, for example, endocytosis or receptor-mediated uptake, whereas others use energy-independent non-endocytic translocation pathways.In some embodiments, the polypeptide targeting moiety binds to a receptor on a cell surface. In some embodiments, the polypeptide binds to the receptor with high affinity. In some embodiments, the receptor is overexpressed on the cell surface. In some embodiments, the polypeptide includes an Arg- Gly-Asp (RGD) motif. In some embodiments, the RGD motif binds integrins. In some embodiments, the RGD motif is a cyclic RGD motif. In some embodiments, the cyclic RGD motif includes the amino acid sequence of RGDFK (SEQ ID NO: 16). In some embodiments, the cyclic RGD may be an internalizing RGD conjugate having an amino acid sequence of CRGDKRGPDC (SEQ ID NO: 17).In some embodiments, the polypeptide targeting moiety targets the circular polyribonucleotide to muscle cells. In some embodiments, this polypeptide is a M12 peptide having the amino acid sequence RRQPPRSISSHP (SEQ ID NO: 18). In some embodiments, the muscle targeting polypeptide is the 7amino acid residue peptide ASSLNIA (SEQ ID NO: 19). In some embodiments, the polypeptide is an LPS-binding protein (LBP) peptide. In some embodiments, the polypeptide is an adipose-homing peptide. In some embodiments, the peptide is an endolytic peptide. For example, the endolytic peptide may have the structure H2N-CKRKKRRQRRRG(dPEG6)GWWG(K / AzidePEG10)-amide. In some embodiments, the peptide is cyclo-F<t>RRRRQ.In some embodiments, the polypeptide is melittin. In some embodiments, the melittin targets tumor cells.In some embodiments, the polypeptide targets a specific cell type; for example, the polypeptide may preferentially target muscle cells (e.g., skeletal muscle cell), blood cells, bone cells, fat cells, skin cells, nerve cells, endothelial cells, stem cells, sex cells, pancreatic cells, or cancer cells. In particular embodiments, the polypeptides target cancer cells (e.g., tumor cells). In some embodiments, the polypeptide targets cells of a specific organ; for example, the polypeptide may preferentially target cells in the heart, lungs, liver, or kidneys.In some embodiments, the polypeptide targeting moiety is an antibody, which may also then be known an antibody drug conjugate. The antibody may target an overexpressed antigen or receptor on the surface of a cell. In some embodiments, the polypeptide targeting moiety is an antibody fragment. In some embodiments, the polypeptide targeting moiety is a single chain Fv molecule (scFv), a diabody, a triabody, a nanobody, a domain antibody, an antibody-like protein scaffold, a Fab fragment, a Fv fragment, a Fab’, a F(ab’)2, a tandem scFv (taFv), or an scFv-Fc. In some embodiments, the polypeptide targeting moiety is a bispecific antibody. In particular embodiments, the peptide targeting moiety is an scFv. In certain embodiments, the polypeptide targeting moiety is a nanobody.In some embodiments, the antibody may bind to a tumor cell-specific antigen. For example, the antibody may be an anti-CD33 antibody, an anti-CD30 antibody, an anti-HER2 antibody, an anti-CD22 antibody, an anti-EGFR antibody, an anti-nectin4 antibody, an anti HER2 antibody, an anti-AXL antibody, an anti-CD74 antibody, an anti-ALK antibody, an anti-PTK antibody, anti-MR antibody, an anti-CD205 antibody, an anti-CD169 antibody, an anti-CD14 antibody, an anti-CD36 antibody, an anti-CD5 antibody, an anti -CD71 antibody, an anti-CD38 antibody, or an anti-prohibin antibody. In some embodiments, the antibody may bind to a tumor tissue-associated antigen. For example, the antibody may be an anti-PSMA antibody, an anti-TM4SF1 antibody, or an anti-CD276 antibody. In particular embodiments, the peptide targeting moiety is an anti-FcRn antibody. In some embodiments, the peptide targeting moiety is an anti- MR antibody. In some embodiments, the peptide targeting moiety is an anti-CD205. In some embodiments, the peptide targeting moiety is an anti-CD14 antibody. In some embodiments, the peptide targeting moiety is an anti-CD36 antibody. In some embodiments, the peptide targeting moiety is an anti- CD5 antibody. In some embodiments, the peptide targeting moiety is an anti-CD71 Fab. In some embodiments, the peptide targeting moiety is an anti-prohibin. In some embodiments, the peptide targeting moiety is an anti-DEC205 antibody.In some embodiments, the nanobody may bind to a tumor cell-specific antigen. For example, the nanobody may be an anti-CD33 nanobody, an anti-CD30 nanobody, an anti-HER2 nanobody, an anti- CD22 nanobody, an anti-EGFR nanobody, an anti-transferrin nanobody, an anti-nectin4 nanobody, an anti HER2 nanobody, an anti-AXL nanobody, and anti-CD74 nanobody, an anti-ALK nanobody, or an anti-PTK nanobody. In some embodiments, the nanobody may bind to a tumor tissue-associated antigen. For example, the antibody may be an anti-PSMA nanobody, an anti-TM4SF1 nanobody, or an anti-CD276 nanobody. In some embodiments, the polypeptide targeting moiety is an anti-transferrin nanobody. In some embodiments, the polypeptide targeting moiety is an anti-EGFR nanobody. In some embodiments, the polypeptide targeting moiety is an anti-HER2 nanobody.Any of the above-described polypeptide moieties may also be biotinylated to facilitate binding to a biotin-binding protein (e.g., avidin, streptavidin, NeutrAvidin).Aptamer Targeting MoietiesIn some embodiments, a targeting moiety is an aptamer. An aptamer is an isolated nucleic acid molecule that binds with high specificity and affinity to a binding moiety or target molecule, such as a protein. An aptamer is a three-dimensional structure held in certain conformation(s) that provides chemical contacts to specifically bind its given target. Although aptamers are nucleic acid-based molecules, there is a fundamental difference between aptamers and other nucleic acid molecules such as genes and mRNA. In the latter, the nucleic acid structure encodes information through its linear base sequence and thus this sequence is of importance to the function of information storage. In complete contrast, aptamer function, which is based upon the specific binding of a target molecule, is not entirely dependent on a conserved linear base sequence (a non-coding sequence), but rather a particular secondary / tertiary / quaternary structure. Any coding potential that an aptamer may possess is fortuitous and is not thought to play a role in the binding of an aptamer to its cognate target. Aptamers are differentiated from naturally occurring nucleic acid sequences that bind to certain proteins. These latter sequences are naturally occurring sequences embedded within the genome of the organism that bind to a specialized sub-group of proteins that are involved in the transcription, translation, and transportation of naturally occurring nucleic acids (e.g., nucleic acid-binding proteins). Aptamers on the other hand are non-naturally occurring nucleic acid molecules. While aptamers can be identified that bind nucleic acid- binding proteins, in most cases such aptamers have little or no sequence identity to the sequences recognized by the nucleic acid-binding proteins in nature. More importantly, aptamers can bind virtually any protein (not just nucleic acid-binding proteins) as well as almost any partner of interest including small molecules, carbohydrates, peptides, etc. For most partners, even proteins, a naturally occurring nucleic acid sequence to which it binds does not exist. For those partners that do have such a sequence, e.g., nucleic acid-binding proteins, such sequences will differ from aptamers as a result of the relatively low binding affinity used in nature as compared to tightly binding aptamers. Aptamers are capable of specifically binding to selected partners and modulating the partner’s activity or binding interactions, e.g., through binding, aptamers may block their partner’s ability to function. The functional property of specific binding to a partner is an inherent property an aptamer. An aptamer can be 6-35 kDa. An aptamer can be from 20 to 500 nucleotides. An aptamer can bind its partner with micromolar to sub-nanomolar affinity, and may discriminate against closely related targets (e.g., aptamers may selectively bind related proteins from the same gene family). In some cases, an aptamer only binds one molecule. In some cases, an aptamer binds family members of a molecule of interest. An aptamer, in some cases, binds to multiple different molecules. Aptamers are capable of using commonly seen intermolecular interactions such as hydrogen bonding, electrostatic complementarities, hydrophobic contacts, and steric exclusion to bind with a specific partner. Aptamers have a number of desirable characteristics for use as therapeutics and diagnostics including high specificity and affinity, low immunogenicity, biological efficacy, and excellent pharmacokinetic properties. An aptamer can include a molecular stem and loop structure formed from the ouhybridization of complementary polynucleotides that are covalently linked (e.g., a hairpin loop structure). The stem includes the hybridized polynucleotides and the loop is the region that covalently links the two complementary polynucleotides. An aptamer can be a linear ribonucleic acid (e.g., linear aptamer) including an aptamer or a circular polyribonucleic acid including an aptamer (e.g., a circular aptamer).In some embodiments, one or more of the aptamer targeting moieties includes aptamer K19, M2 aptamer, Ly75 aptamer, aptamer CTApt-268, Aptamer14, Aptamer NAFLD01 , TfnR-aptamer, DEC205 aptamer (GGGAGGUGUGUUAGCACACGAUUCAUAAUCAGCUACCCUCCC (SEQ ID NO: 20)),, or MA33 aptamer (GTTACCGCGGTGAAGGGTGGATGTGTCTGGA (SEQ ID NO: 21)), A01 B aptamer (CAGGAGCCGAGAACCGGTTGGTGGGTAATCCTGTTAGCGC (SEQ ID NO: 22)), HG19 aptamer (GGATAGGGATTCTGTTGGTCGGCTGGTTGGTATCC (SEQ ID NO: 23)), C2.min aptamer (GGGGGAUCAAUCCAAGGGACCCGGAAACGCUCCCUUACACCCC (SEQ ID NO: 87)), DC aptamer (AGGGTTACTCGGAT (SEQ ID NO: 24)), A2 aptamer (GAAGAGTAGATGAAACGTTTTTTCGCCCGATAAAAGGGACGTGCGTCAGACA (SEQ ID NO: 25)), or WAZ aptamer (GGGUUCUACGAUAAACGGUUAAUGACCAGCUUAUGGCUGGCAGUUCCC (SEQ ID NO: 26)), or A1411 aptamer (GGTGGTGGTGGTTGTGGTGGTGGTGG (SEQ ID NO: 95).Any of the above-described aptamer targeting moieties may also be biotinylated to facilitate binding to a biotin-binding protein (e.g., avidin, streptavidin, NeutrAvidin).LinkersIn some embodiments, a linker provides space, rigidity, and / or flexibility between the moiety which forms a complex with the circular polyribonucleotide and the targeting moiety described herein. In some embodiments, the disclosure provides a complex including a circular polyribonucleotide, a moiety that binds specifically to a region of the circular polyribonucleotide, two or more linkers (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more), and two or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) targeting moieties (e.g., X-(L-B)Z, wherein z is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). In some embodiments, the linkers are the same linker. In some embodiments, the linkers are different from one another. In some embodiments, some of the linkers are the same linker and some of the linkers are different from one another.In some embodiments, a linker may be a bond, e.g., a covalent bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-N bond, a N-N bond, a C-S bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1- 180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). In some embodiments, a linker includes no more than 250 non-hydrogen atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1- 30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1- 130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 non-hydrogen atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non- hydrogen atom(s)). In some embodiments, the backbone of a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60,1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). In some embodiments, the linker includes from 1 to 1000 atoms (e.g., from 1 to 750 atoms, 1 to 500 atoms, 1 to 250 atoms, 1 to 100 atoms, 1 to 75 atoms, 1 to 50 atoms, 1 to 25 atoms, and 1 to 10 atoms). In some embodiments, the linker includes from 1 to 100 atoms. In some embodiments, the linker includes from 1 to 50 atoms. In some embodiments, the linker includes from 1 to 25 atoms.In some embodiments, the linker is linear and includes from 1 to 1000 atoms (e.g., from 1 to 750 atoms, 1 to 500 atoms, 1 to 250 atoms, 1 to 100 atoms, 1 to 75 atoms, 1 to 50 atoms, 1 to 25 atoms, and 1 to 10 atoms). In some embodiments, the linker is linear and includes from 1 to 100 atoms. In some embodiments, the linker is linear and includes from 1 to 50 atoms. In some embodiments, the linker is linear and includes from 1 to 25 atoms.In some embodiments, the linker is branched, and each branch includes from 1 to 1000 atoms (e.g., from 1 to 750 atoms, 1 to 500 atoms, 1 to 250 atoms, 1 to 100 atoms, 1 to 75 atoms, 1 to 50 atoms, 1 to 25 atoms, and 1 to 10 atoms). In some embodiments, the linker is branched, and each branch includes from 1 to 100 atoms. In some embodiments, the linker is branched, and each branch includes from 1 to 50 atoms. In some embodiments, the linker is branched, and each branch includes from 1 to 25 atoms.The “backbone” of a linker refers to the atoms in the linker that together form the shortest path from one part of the conjugate to another part of the conjugate. The atoms in the backbone of the linker are directly involved in linking one part of the conjugate to another part of the conjugate. For examples, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the conjugate to another part of the conjugate.In some embodiments, a linker includes a heteroatom, such as a nitrogen, sulfur, oxygen, phosphorus, silicon, or boron atom. In some embodiments, the linker includes a cyclic group (e.g., an aryl, heteroaryl, cycloalkyl, or heterocyclyl group). In some embodiments, a linker includes a functional group such as an amide, ketone, ester, ether, thioester, thioether, thiol, hydroxyl, amine, cyano, nitro, azide, triazole, pyrroline, p-nitrophenyl, alkene, or alkyne group. Any atom within a linker may be substituted or unsubstituted. In some embodiments, a linker includes an arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alky ny larylalky ny I, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alky ny lary I, alkylheteroaryl, alkenylheteroaryl, or alkynylhereroaryl group.In some embodiments, a linker includes a polyethylene glycol group (e.g., PEG1 , PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG10, PEG12, PEGU, PEG16, PEG18, PEG20, PEG24, PEG28, PEG32, PEG100, PEG200, PEG250, PEG500, PEG600, PEG700, PEG750, PEG800, PEG900,PEG1000, PEG2000, PEG3000, PEG4000, PEG5000, PEG6000, PEG7000, PEG8000, PEG9000, and PEG10000). In some embodiments, the linker includes at least one PEG unit. For example, the linker may include PEG2 to PEG10000 (e.g., PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG10, PEG12, PEGU, PEG16, PEG18, PEG20, PEG24, PEG28, PEG32, PEG100, PEG200, PEG250, PEG500, PEG600, PEG700, PEG750, PEG800, PEG900, PEG1000, PEG2000, PEG3000, PEG4000, PEG5000, PEG6000, PEG7000, PEG8000, PEG9000, and PEG10000).In some embodiments, a linker includes a triethylene glycol group (e.g., TEG1 , TEG2, TEG3, TEG4, TEG5, TEG6, TEG7, TEG8, TEG10, TEG12, TEG14, TEG16, TEG18, TEG20, TEG24, TEG28, TEG32, TEG100, TEG200, TEG250, TEG500, TEG600, TEG700, TEG750, TEG800, TEG900, TEG1000, TEG2000, TEG3000, TEG4000, TEG5000, TEG6000, TEG7000, TEG8000, TEG9000, and TEG10000). In some embodiments, the linker includes at least one TEG unit. For example, the linker may include TEG2 to TEG10000 (e.g., TEG2, TEG3, TEG4, TEG5, TEG6, TEG7, TEG8, TEG10, TEG12, TEG14, TEG16, TEG18, TEG20, TEG24, TEG28, TEG32, TEG100, TEG200, TEG250, TEG500, TEG600, TEG700, TEG750, TEG800, TEG900, TEG1000, TEG2000, TEG3000, TEG4000, TEG5000, TEG6000, TEG7000, TEG8000, TEG9000, and TEG10000).The composition includes at least one linker that connects the targeting moiety to the moiety that binds or conjugates to the circular polyribonucleotide. In some embodiments, the moiety that binds or conjugates to the circular polyribonucleotide is connected to one or more targeting moieties, through a linker as described herein. The linker may be monovalent or multivalent, e.g., bivalent, trivalent, tetravalent, or pentavalent. In some embodiments, the linker includes a structure selected from:wherein q2A, q2B, q3A, q3B, q4A, q4B, q5A, q5B and q5C represent independently for each occurrence 0-20 and wherein the repeating unit can be the same or different; P2A, P2B, P3A, P3B, P4A, P4B, P5A, P5B, are each independently for each occurrence absent, CO, NH,O, S, OC(O), NHC(O), CH2, CH2NH or CH2O; Q2A, Q2B, Q3A, Q3B, Q4A, Q4B, Q5A, Q5B, Q5Careindependently for each occurrence absent, alkylene, substituted alkylene wherein one or more methylenes can be interrupted or terminated by one or more of( ) ( ) ( ) ( )occurrence a targeting moiety; and Rais H or amino acid side chain.In some embodiments, the linker includes:wherein L5A, L5Band L5Crepresent a targeting moiety, e.g., as described herein.In some embodiments, molecules that may be used to make linkers include at least two functional groups, e.g., two carboxylic acid groups. In some embodiments of a trivalent linker, two arms of a linker may contain two dicarboxylic acids. In some embodiments, dicarboxylic acid molecules may be used as linkers (e.g., a dicarboxylic acid linker).Examples of dicarboxylic acids molecules that may be used to form linkers include, but are not limited to,wherein n is an integer from 1 to 20 (e.g., n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20).Other examples of dicarboxylic acids molecules that may be used to form linkers include, but are not limited to,In some embodiments, dicarboxylic acid molecules, such as the ones described herein, may be further functionalized to contain one or more additional functional groups. Dicarboxylic acids may be further functionalized, for example, to provide an attachment point to one or more targeting moieties and a moiety which forms a complex with the circular polyribonucleotide.In some embodiments, when the targeting moiety is attached to a moiety which forms a complex with the targeting circular polyribonucleotide, the linking group may include a moiety including a carboxylic acid moiety and an amino moiety that are spaced by from 1 to 25 atoms. Examples of such linking groups include, but are not limited to,wherein n is an integer from 1 to 20 (e.g., n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20). In some embodiments, a linking group may include a moiety including a carboxylic acid moiety and an amino moiety, such as the ones described herein, may be further functionalized to contain one or more additional functional groups. Such linking groups may be further functionalized, for example, to provide an attachment point to a targeting moiety.In some embodiments, when the targeting moiety is attached to the moiety which forms a complex with the circular polyribonucleotide, the linking group may include a moiety including two or amino moieties (e.g., a diamino moiety) that are spaced by from 1 to 25 atoms. Examples of such linking groups include, but are not limited to,wherein n is an integer from 1 to 20 (e.g., n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20).In some embodiments, a linking group may include a diamino moiety, such as the ones described herein, may be further functionalized to contain one or more additional functional groups. Such diamino linking groups may be further functionalized, for example, to provide an attachment point to a targeting moiety.In some embodiments, a molecule containing an azide group may be used to form a linker, in which the azide group may undergo cycloaddition with an alkyne to form a 1 ,2,3-triazole linkage. In some embodiments, a molecule containing an alkyne group may be used to form a linker, in which the alkyne group may undergo cycloaddition with an azide to form a 1 ,2,3-triazole linkage. In some embodiments, a molecule containing a maleimide group may be used to form a linker, in which the maleimide group may react with a cysteine to form a C-S linkage. In some embodiments, a molecule containing one or more haloalkyl groups may be used to form a linker, in which the haloalky I group may form a covalent linkage, e.g., C-N and C-0 linkages, with a targeting moiety.In some embodiments, the linker may be an oligonucleotide, which includes a string of nucleic acids. In some embodiments, the targeting moiety described herein include a string of nucleic acids, which is in turn linked a moiety which complexes with the circular polyribonucleotide. The linker can have any sequence, for example, the sequence of the oligonucleotide can be a random sequence, or a sequence specifically chosen for its molecular or biochemical properties. In some embodiments, the linker includes 20 one or more series of consecutive adenine (A), cytosine (C), guanine (G), thymine (T), uracil (U), or analog thereof. In some embodiments, the linker consists of a series of consecutive adenine (A), cytosine (C), guanine (G), thymine (T), uracil (U), or analog thereof. In some embodiments, the string of nucleic acids includes from 1 to 50 nucleic acid residues (e.g., from 2 to 40, 2 to 30, 2 to 20, 2 to 10, 2 to 5, 5 to 50, 10 to 50, 20 to 50, 30 to 50, or 40 to 50 residues). In some embodiments, the string of nucleic acids includes from 5 to 30 nucleic acid residues (e.g., from 5 to 25, 5 to 20, 5 to 15, 5 to 10, 10 to 30, 15 to 30, 20 to 30, or 25 to 30 residues). In some embodiments, the linker includes one or more guanines, for example from 1-10 guanines (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 guanine residues).In some embodiments, the linker is a polypeptide. For example, the linker may include at least one amino acid. In some embodiments, the polypeptide linker may include from two to 100 amino acid residues (e.g., from 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 10 to 100, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, or 90 to 100 amino acid residues). In certain embodiments, the linker is a single amino acid (e.g., any naturally occurring amino acid such as Cys). In some embodiments, the linker includes a series of glycine residue to form a polyglycine linker. In some embodiments, the linker includes an amino acid sequence of (G ly) n, wherein nmay be from 2 to 20 residues (e.g., from 2 to 15, 2 to 10, 2 to 5, 5 to 20, 10 to 20, or 15 to 20 glycine residues). Examples of polyglycine linkers include but are not limited to GGG, GGGA (SEQ ID NO: 27), GGGG (SEQ ID NO: 28), GGGAG (SEQ ID NO: 29), GGGAGG (SEQ ID NO: 30), GGGAGGG (SEQ ID NO: 31), GGAG (SEQ ID NO: 32),GGSG (SEQ ID NO: 33), AGGG (SEQ ID NO: 34), SGGG (SEQ ID NO: 35), GGAGGA (SEQ ID NO: 36), GGSGGS (SEQ ID NO: 37), GGAGGAGGA (SEQ ID NO: 38), GGSGGSGGS (SEQ ID NO: 39), GGAGGAGGAGGA (SEQ ID NO: 40), GGSGGSGGSGGS (SEQ ID NO: 41), GGAGGGAG (SEQ ID NO: 42), GGSGGGSG (SEQ ID NO: 43), GGAGGGAGGGAG (SEQ ID NO: 44), GGSGGGSGGGSG (SEQ ID NO: 45), GGGGAGGGGAGGGGA (SEQ ID NO: 46), GGGGSGGGGSGGGGS (SEQ ID NO: 47), and GGGSGGGS (SEQ ID NO: 48). In other embodiments, the polypeptide linker is a glycine-rich polypeptide such as a polypeptide having the sequence [Gly-Gly- Gly-Gly-Ser]n(SEQ ID NO: 49) where n is 1 , 2, 3, 4, 5 or 6 is used. In some embodiments, the polypeptide linker is a serine-rich polypeptide linker. Serine rich peptide linkers include those of the formula [X-X-X-X-Gly]y(SEQ ID NO: 50), where up to two of the X are Thr, and the remaining X are Ser, and y is 1 to 5 (e.g., Ser-Ser-Ser-Ser-Gly (SEQ ID NO: 51), where y is greater than 1). In some cases, the linker is a single amino acid (e.g., any amino acid, such as Gly or Cys).Amino acid linkers may be selected for flexibility (e.g., flexible or rigid) or may be selected on the basis of charge (e.g., positive, negative, or neutral). Flexible linkers typically include those with Gly resides (e.g., [Gly-Gly-Gly-Gly-Ser]nwhere n is 1 , 2, 3, 4, 5 or 6). Other linkers include rigid linkers (e.g., PAPAP (SEQ ID NO: 52) and (PT)nP (SEQ ID NO: 53), where n is 2, 3, 4, 5, 6, or 7) and a-helical linkers (e.g., A(EAAAK)nA (SEQ ID NO: 54), where n is 1 , 2, 3, 4, or 5).Examples of suitable linkers are succinyl, Lys, Glu, and Asp, or a dipeptide such as Gly-Lys. When the linker is succinyl, one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the other carboxyl group thereof may, for example, form an ester bond with a hydroxyl group of opioid moiety. When the linker is Lys, Glu, or Asp, the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the amino group thereof may, for example, form an amide bond with a carboxyl group of the opioid moiety. When Lys is used as the linker, a further linker may be inserted between the ε-amino group of Lys and the opioid moiety. In one particular embodiment, the further linker is succinyl acid, which can form an amide bond with the ε- amino group of Lys and an ester bond with a hydroxyl group present in the opioid moiety. In one embodiment, the further linker is Glu or Asp (e.g., which forms an amide bond with the ε-amino group of Lys and an ester or amide bond with a hydroxyl or amino group present in the opioid moiety). In other embodiments, the peptide linker is a branched polypeptide.In some embodiments, the linker is an enzymatically cleavable linker. A cleavable linking group is one which is sufficiently stable outside the cell, but which upon entry into a target cell is cleaved to release the two parts the linker is holding together. In a preferred embodiment, the cleavable linking group is cleaved at least about 10 times, 20, times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or more, or at least about 100 times faster in a target cell or under a first reference condition (which can, e.g., be selected to mimic or represent intracellular conditions) than in the blood of a subject, or under a second reference condition (which can, e.g., be selected to mimic or represent conditions found in the blood or serum).Cleavable linking groups are susceptible to cleavage agents, e.g., pH, redox potential or the presence of degradative molecules. Generally, cleavage agents are more prevalent or found at higherlevels or activities inside cells than in serum or blood. Examples of such degradative agents include: redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as mercaptans, present in cells, that can degrade a redox cleavable linking group by reduction; esterases; endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower; enzymes that can hydrolyze or degrade an acid cleavable linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases.A cleavable linkage group, such as a disulfide bond can be susceptible to pH. The pH of human serum is 7.4, while the average intracellular pH is slightly lower, ranging from about 7.1 -7.3. Endosomes have a more acidic pH, in the range of 5.5-6.0, and lysosomes have an even more acidic pH at around 5.0. Some linkers will have a cleavable linking group that is cleaved at a preferred pH, thereby releasing a cationic lipid from the ligand inside the cell, or into the desired compartment of the cell.A linker can include a cleavable linking group that is cleavable by a particular enzyme. The type of cleavable linking group incorporated into a linker can depend on the cell to be targeted. For example, a liver-targeting ligand can be linked to a cationic lipid through a linker that includes an ester group. Liver cells are rich in esterases, and therefore the linker will be cleaved more efficiently in liver cells than in cell types that are not esterase-rich. Other cell-types rich in esterases include cells of the lung, renal cortex, and testis. Linkers that contain peptide bonds can be used when targeting cell types rich in peptidases, such as liver cells and synoviocytes.In general, the suitability of a candidate cleavable linking group can be evaluated by testing the ability of a degradative agent (or condition) to cleave the candidate linking group. It will also be desirable to also test the candidate cleavable linking group for the ability to resist cleavage in the blood or when in contact with other non-target tissue. Thus, one can determine the relative susceptibility to cleavage between a first and a second condition, where the first is selected to be indicative of cleavage in a target cell and the second is selected to be indicative of cleavage in other tissues or biological fluids, e.g., blood or serum. The evaluations can be carried out in cell free systems, in cells, in cell culture, in organ or tissue culture, or in whole animals. It can be useful to make initial evaluations in cell-free or culture conditions and to confirm by further evaluations in whole animals. In preferred embodiments, useful candidate compounds are cleaved at least about 2, 4, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood or serum (or under in vitro conditions selected to mimic extracellular conditions).In one embodiment, a cleavable linking group is a redox cleavable linking group that is cleaved upon reduction or oxidation. An example of reductively cleavable linking group is a disulphide linking group (-S-S-). To determine if a candidate cleavable linking group is a suitable “reductively cleavable linking group,” or for example is suitable for use with a particular RNA moiety and particular targeting agent one can look to methods described herein. For example, a candidate can be evaluated by incubation with dithiothreitol (DTT), or other reducing agent using reagents know in the art, which mimic the rate of cleavage which would be observed in a cell, e.g., a target cell. The candidates can also be evaluated under conditions which are selected to mimic blood or serum conditions. In one, candidate compounds are cleaved by at most about 10% in the blood. In other embodiments, useful candidate compounds are degraded at least about 2, 4, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood (orunder in vitro conditions selected to mimic extracellular conditions). The rate of cleavage of candidate compounds can be determined using standard enzyme kinetics assays under conditions chosen to mimic intracellular media and compared to conditions chosen to mimic extracellular media.In another embodiment, a cleavable linker includes a phosphate-based cleavable linking group. A phosphate-based cleavable linking group is cleaved by agents that degrade or hydrolyze the phosphate group. An example of an agent that cleaves phosphate groups in cells are enzymes such as phosphatases in cells. Examples of phosphate-based linking groups are -O-P(O)(ORk)-O-, -O-P(S)(ORk)- O-, -O-P(S)(SRk)-O-, -S-P(O)(ORk)-O-, -O-P(O)(ORk)-S-, -S-P(O)(ORk)-S-, -O-P(S)(ORk)-S-, -S- P(S)(ORk)-O-, -O-P(O)(Rk)-O-, -O-P(S)(Rk)-O-, -S-P(O)(Rk)-O-, -S-P(S)(Rk)-O-, -S-P(O)(Rk)-S-, -O- P(S)( Rk)-S-. Preferred embodiments are -O-P(O)(OH)-O-, -O-P(S)(OH)-O-, -O-P(S)(SH)-O-, -S- P(O)(OH)-O-, -O-P(O)(OH)-S-, -S-P(O)(OH)-S-, -O-P(S)(OH)-S-, -S-P(S)(OH)-O-, -O-P(O)(H)-O-, -O- P(S)(H)-O-, -S-P(O)(H)-O, -S-P(S)(H)-O-, -S-P(O)(H)-S-, -O-P(S)(H)-S-. A preferred embodiment is -O- P(O)(OH)-O-. These candidates can be evaluated using methods analogous to those described above.In another embodiment, a cleavable linker includes an acid cleavable linking group. An acid cleavable linking group is a linking group that is cleaved under acidic conditions. In preferred embodiments acid cleavable linking groups are cleaved in an acidic environment with a pH of about 6.5 or lower (e.g., about 6.0, 5.75, 5.5, 5.25, 5.0, or lower), or by agents such as enzymes that can act as a general acid. In a cell, specific low pH organelles, such as endosomes and lysosomes can provide a cleaving environment for acid cleavable linking groups. Examples of acid cleavable linking groups include but are not limited to hydrazones, esters, and esters of amino acids. Acid cleavable groups can have the general formula -C=NN-, C(O)O, or -OC(O). A preferred embodiment is when the carbon attached to the oxygen of the ester (the alkoxy group) is an aryl group, substituted alkyl group, or tertiary alkyl group such as dimethyl pentyl or t-butyl. These candidates can be evaluated using methods analogous to those described above.In another embodiment, a cleavable linker includes an ester-based cleavable linking group. An ester-based cleavable linking group is cleaved by enzymes such as esterases and amidases in cells. Examples of ester-based cleavable linking groups include but are not limited to esters of alkylene, alkenylene and alkynylene groups. Ester cleavable linking groups have the general formula -C(O)O-, or - OC(O)-. These candidates can be evaluated using methods analogous to those described above.In yet another embodiment, a cleavable linker includes a peptide-based cleavable linking group. A peptide-based cleavable linking group is cleaved by enzymes such as peptidases and proteases in cells. Peptide-based cleavable linking groups are peptide bonds formed between amino acids to yield oligopeptides (e.g., dipeptides, tripeptides etc.) and polypeptides. Peptide-based cleavable groups do not include the amide group (-C(O)NH-). The amide group can be formed between any alkylene, alkenylene or alkynelene. A peptide bond is a special type of amide bond formed between amino acids to yield peptides and proteins. The peptide-based cleavage group is generally limited to the peptide bond (i.e., the amide bond) formed between amino acids yielding peptides and proteins and does not include the entire amide functional group. Peptide-based cleavable linking groups have the general formula - NHCHRAC(O)NHCHRBC(O)-, where RA and RB are the R groups of the two adjacent amino acids. These candidates can be evaluated using methods analogous to those described above.In some additional embodiments, the linker further includes a biotin-binding protein (e.g., avidin, streptavidin, NeutrAvidin). For example, the biotin-binding protein may be avidin. In some embodiments,the avidin binds a biotinylated targeting moiety, as shown for example in FIG. 10. In some embodiments, the avidin binds 1 , 2, 3, 4, or more biotinylated targeting moieties. In some embodiments, the biotinylated targeting moiety includes a lipid, small molecule, carbohydrate, polypeptide, and / or aptamer. In some embodiments, two or more of the biotinylated targeting moieties are the same targeting moiety. In some embodiments, two or more of the biotinylated targeting moieties that are different targeting moieties from one another.Photoreactive Crosslinking AgentsThe disclosure provides a complex that includes a circular polyribonucleotide, a moiety that binds specifically to a region of the circular polyribonucleotide, a photoreactive crosslinking agent, a linker, and targeting moiety. The photoreactive crosslinking agent provides a covalent attachment between the circular polyribonucleotide and the moiety that attaches to a region of the circular polyribonucleotide upon irradiation with light, e.g., at a first wavelength. In some embodiments, the photoreactive crosslinking agent is reversibly attached. For example, the covalent attachment may be removed upon irradiation with light, e.g., at a second wavelength that is different from the first wavelength. In some embodiments, the photoreactive crosslinking agent is attached to the end of the moiety. In some embodiments, the photoreactive crosslinking agent is located at an internal position within the moiety.In some embodiments, the disclosure provides a complex including a circular polyribonucleotide, a moiety that binds specifically to a region of the circular polyribonucleotide and includes one or more (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) photoreactive crosslinking agents, a linker, and a targeting moiety. In some embodiments, the photoreactive crosslinking agents are the same photoreactive crosslinking agent. In some embodiments, the photoreactive crosslinking agents are different from one another. In some embodiments, each of the photoreactive crosslinking agents is located at an internal position within the moiety. In some embodiments, at least one of the photoreactive crosslinking agents is attached to an end of the moiety. In some embodiments, at least one of the photoreactive crosslinking agents is attached to a second end of the moiety. The photoreactive crosslinking agent may be a photoreactive nucleotide analog or a photoreactive amino acid analog.Photoreactive Nucleotide AnalogsIn some embodiments, the moiety that specifically binds a region of the circular polyribonucleotide and includes one or more photoreactive crosslinking agents is an oligonucleotide. Oligonucleotide binding moieties are described in greater detail in a later section of the Detailed Description. In some embodiments, the moiety that specifically binds a region of the circular polyribonucleotide and includes one or more photoreactive crosslinking agent is an oligonucleotide, wherein each of the one or more photoreactive crosslinking agents is a photoreactive nucleotide analog. In some embodiments, each of the one or more photoreactive nucleotide analogs replaces a single nucleotide within the oligonucleotide. Each of the one or more photoreactive nucleotide analogs may include a nucleotide or nucleoside modified to contain a photoreactive group. In some embodiments, the photoreactive nucleotide analog crosslinks to a complementary ribonucleotide or a ribonucleotide located 1 base upstream or 1 base downstream of the opposing ribonucleotide within the circular polyribonucleotide upon photoirradiation. The disclosure provides photoreactive nucleotide analogs included within the oligonucleotide. Photoreactive nucleotide analogs include, for example, 4-thiouridene(4sU), 5-bromo-2’-deoxyuridine (BrdU), coumarin derivatives, D-threoninol (CNVD) derivatives, 3- cyanovinylcarbazole nucleoside (CNVK) derivatives, diazirene derivatives, phenylselenide derivatives, psoralen derivatives, or pyranovinylcarbazole (PCX) derivatives.In some embodiments, the photoreactive crosslinking agent includes 5-bromo-2’-deoxyuridine (BrdU), a carbazole, a psoralen, a coumarin, 4’-thiouridine, a diazirine, a pheylselenide, a furan, or an abasic site.In some embodiments, the carbazole is 3-cyanovinylcarbazole, 4-methylpyranocarbazole, or pyranocarbazole.In some embodiments, the coumarin is 7-hydroxycoumarin.In some embodiments, the photoreactive nucleotide analog is one disclosed in U.S. Pat. No. 8,481 ,714, the disclosure of which is hereby incorporated by reference in its entirety.In some embodiments, the photoreactive crosslinking agent includes a compound of Formula (I):wherein, in the formula (I), Rarepresents a cyano group, an amide group, a carboxyl group, a C2-C7 alkoxycarbonyl group, or hydrogen, wherein, in the formula (I), Ri and R2 each independently represent a cyano group, an amide group, a carboxyl group, a C2-C7 alkoxycarbonyl group, or hydrogen, and wherein, in the formula (I), Rb represents a sugar, a polysaccharide, a polyether, a polyol, a polypeptide chain, or a water-soluble synthetic polymer.In some embodiments, the photoreactive crosslinking agent is the compound according to Formula (I), wherein R& is represented by any one of Formulae (II) - (V):3, 4, or 5). In some embodiments, the photoreactive crosslinking agent is the compound of any one ofFormulae (VI) - (X):wherein, in Formula (IX), n is represented as any number 2 to 5 (e.g., 2, 3, 4, or 5).In some embodiments, the photoreactive crosslinking agent includes a compound of Formulawherein, in Formula (XII), R1represents a hydrogen or methyl group, wherein, in Formula (XII), R2 represents a hydrogen or methoxy group, wherein in Formula (XII), R3 represents a hydrogen, a methyl group, or a methoxy group, wherein in Formula (XII), R4 represents an aminomethyl group, an azidomethyl group, or a hydrogen group, wherein in Formula (XII), R5 represents a hydrogen or methyl group. In some embodiments, the photoreactive crosslinking agent is the compound of any one of Formulae (XIII) - (XVII):In some embodiments, the photoreactive nucleotide analog may be 4sU. The structure of 4sU mimics the structure of uridine analogs but gains photoreactive properties by replacing the carbonyl oxygen at position 4 of the ring with a sulfur atom. Upon irradiation with light having a wavelength of 356 nm, photoreactive 4sU within an oligonucleotide covalently binds to a nearby cytosine nucleobase through a [2+2] cycloaddition reaction.In some embodiments, the photoreactive nucleotide analog may be BrdU. Upon irradiation with light having wavelength of 308 nm, BrdU generates 2’-deoxyuridin-5-yl radicals.In some embodiments, the photoreactive nucleotide analog may be a coumarin, a coumarin analog, or a derivative thereof. Coumarin and derivatives thereof located within the oligonucleotide covalently bind to a nearby thymine nucleobase through a [2+2] cycloaddition reaction upon irradiation with light having a wavelength of 250 nm, resulting in the formation of a syn-cycloaddition photo-adduct. Irradiating the syn-cycloaddition photo-adduct with light having a wavelength of 254 nm reverses the reaction. An example of a coumarin derivative that is a photoreactive nucleotide analog is 7- hydroxycoumarin (see, e.g., Elskens et al., RSC Chem. Biol. 2, 410-422, 2021 , which is hereby incorporated by reference in its entirety).In some embodiments, the photoreactive nucleotide analog may beCNVK or derivatives thereof.CNVK and derivatives thereof within an oligonucleotide have a vinyl group that is aligned with the C5-C6 double bond of a pyrimidine nucleobase located 1 base downstream of an opposing nucleotide within anearby oligonucleotide. Upon irradiation with light having a wavelength of 366 nm,CNVK or a derivative thereof covalently binds with a nearby pyrimidine-containing nucleobase through a [2+2] cycloaddition, resulting in the formation of the photo-adduct. Pyrimidine-containing nucleobases include cytosine, thymine, and uracil. Irradiating the photo-adduct with light having a wavelength of 312 nm reverses the reaction. Irradiation with longer wavelength light, as compared to the 254 nm wavelength light used for reversing photo-adduct formation, circumvents the photo-induced DNA damage at shorter wavelengths. The trans isomer compared to the cis isomer ofCNVKis the reactive species for photoreactive crosslinking (see, e.g., Fujimoto et al. J. Am. Chem. Soc.135, 16161-16167, 2013 which is hereby incorporated by reference in its entirety). Another example of aCNVK derivative is n-CNVK which includes a linker of variable lengths (n = 2-5). Upon irradiation, n-CNVK can form a covalent bond with a nearby pyrimidine nucleobase at locations other than the 1 base downstream position of an opposing nucleotide depending on the linker length (see, e.g., Fujimoto et al. Photochem. Photobiol. Sci. 19, 776-782, 2020, which is hereby incorporated by reference in its entirety).In some embodiments, the photoreactive nucleotide analog may beCNVD.CNVD and derivatives thereof within an oligonucleotide have a vinyl group that is aligned with the C5-C6 double bond of a pyrimidine nucleobase located 1 base downstream of an opposing nucleotide within a nearby oligonucleotide.CNVD is a derivative ofCNVK that has the same chemical structure ofCNVK except for a D- threoninol linker in the place of the deoxyribose sugar which acts to increase the flexibility as compared to CNVK, increasing the photo-induced crosslinking reaction rate due to minimization of entropic losses during hybridization (see, e.g., Sakamoto et al. Org. Lett. 17, 936-939, 2015, which is hereby incorporated by reference in its entirety). Upon irradiation with light having a wavelength of 365 nm,CNVD or a derivative thereof covalently binds with a nearby pyrimidine-containing nucleobase through a [2+2] cycloaddition, resulting in the formation of the photo-adduct. Pyrimidine-containing nucleobases include cytosine, thymine, and uracil. Irradiating the photo-adduct with light having a wavelength of 312 nm reverses the reaction. Irradiation with longer wavelength light, as compared to the 254 nm wavelength light used for reversing photo-adduct formation, circumvents photo-induced DNA damage at shorter wavelengths.In some embodiments, the photoreactive nucleotide analog may be a diazirene derivative. Upon irradiation with light having a wavelength of 365 nm, a diazirene derivative becomes a reactive carbene intermediate. The reactive carbene intermediates rapidly form a covalent bond with a nearby nucleobase through C-C, C-H, O-H, or X-H (X = heteroatom) insertions. The reactive carbene intermediate can react with all nucleobases, including adenine, cytosine, guanine, thymine, and uracil, forming a covalent attachment with a nearby nucleobase. An example of a diazirene derivative is 3-phenyl-3-trifluoromethyl-which is attached to the sugar ring through an acetal linkage (see, e.g., Nakamoto et al. J. Org. Chem. 79, 2463-2472, 2014, which is hereby incorporated by reference in its entirety).In some embodiments, the photoreactive nucleotide analog may be a phenyl selenide analog. Upon irradiation with light having a wavelength of 350 nm, phenyl selenide becomes a radical intermediate which has the capability of alkylating the N1 or N6 position of nearby purine nucleobases, including adenine. An example of a phenyl selenide analog is phenyl selenide-modified 2’-deoxythymidine (see, e.g., Elskens et al., RSC Chem. Biol. 2, 410-422, 2021 , which is hereby incorporated by reference in its entirety).In some embodiments, the photoreactive nucleotide analog may be a psoralen analog or a derivative thereof. Psoralen and derivatives thereof are tricyclic compounds that may intercalate in any AT or AU region of hybridized DNA and RNA sequences, respectively. Psoralen and derivatives thereof react through their furan or pyrone photoreactive site to covalently bind the C5-C6 double bond of pyrimidine residues. This forms a covalent attachment between two nearby pyrimidine nucleobases through a [2+2] cycloaddition reaction upon irradiation with light having a wavelength of 365 nm, resulting in the formation of a cyclobutene photo-adduct. The resulting cyclobutene photo-adduct may be in the syn- or cis- configuration. Pyrimidine residues are present among cytosine, thymine, and uracil bases. Irradiating the cyclobutene photo-adduct with light having a wavelength of 254 nm reverses the reaction. An example of a psoralen derivative is 4’-aminomethyltrioxsalen (see, e.g., Velema et al. JACS Au 3, 316-332, 2023, which is hereby incorporated by reference in its entirety).In some embodiments, the photoreactive nucleotide analog may be pyranocarbazole and derivatives thereof, such as pyranocarbozole nucleoside (PCX). The photoreactive pyranocarbozole and derivatives thereof within an oligonucleotide include a vinyl group that is aligned with the C5-C6 double bond of a pyrimidine nucleobase located 1 base downstream of an opposing nucleotide within a nearby oligonucleotide. Upon irradiation with light having a wavelength of 400 nm,PCX covalently binds with a nearby, pyrimidine-containing nucleobase through a [2+2] cycloaddition, resulting in the formation of the photo-adduct. Pyrimidine-containing nucleobases include cytosine, thymine, and uracil. Irradiating the photo-adduct with light having a wavelength of 312 nm reverses the reaction. Irradiation with longer wavelength light, as compared to the 254 nm wavelength light used for reversing photo-adduct formation, circumvents the photo-induced DNA damage at shorter wavelengths. An example of a pyranocarbozole derivative isPCX with a D-threoninol linker in the place of the deoxyribose sugar (PCXD) which acts to increase the flexibility as compared toPCX, increasing the photo-induced crosslinking reaction rate due to minimization of entropic losses during hybridization (see, e.g., Fujimoto et al. RSC Adv. 9, 30693-30697, 2019, which is hereby incorporated by reference in its entirety). Another example of a pyranocarbozole derivative ispcX that includes a methyl group at the 4-position ofPCX. 4-methylpyranocarbozole nucleoside (MEPK) is able to differentiate between thymine and cytosine, enabling selectivity toward thymine (see, e.g., Mihara et al. Org. Biomol. Chem. 19, 9860-9866, 2021 , which is hereby incorporated by reference in its entirety).In some embodiments, the oligonucleotide may include another photoreactive nucleotide analog which allows for the oligonucleotide binding moiety to covalently attach to the polyribonucleotide described herein. For a review of certain photoreactive nucleotide analogs, see, e.g., Elskens et al., RSC Chem. Biol. 2, 410-422, 2021 ; Tavakoli et al., RSC Adv. 12, 6484-6507, 2022; and Velema et al. JACS Au 3, 316-332, 2023.Photoreactive Amino Acid AnalogsIn some embodiments, the moiety that specifically binds a region of the circular polyribonucleotide is a polypeptide. In some embodiments, the moiety includes one or more photoreactive amino acid analogs. In some embodiments, the photoreactive amino acid analog replaces an amino acid within the polypeptide. The one or more photoreactive amino acid analogs may include an amino acid modified to contain a photoreactive group. Photoreactive nucleotide analogs include, for example, arylazide-based, benzophenone-based, or diazirene-based unnatural amino acids ory I) et h oxy] carbonyl-lysine.In some embodiments, the photoreactive amino acid analog may be an aryl azide-based unnatural amino acid. Upon irradiation with light having a wavelength of 250-350 nm, aryl azide-based unnatural amino acids generate a reactive nitrene intermediate. The reactive nitrene intermediate can covalently bond with a nearby nucleobase through C-H and X-H insertions. An example of an arylazide- based unnatural amino acid is tetrafluorophenylazide (see, e.g., Smith et al Future Med. Chem. 7, 159- 183, 2015, which is hereby incorporated by reference in its entirety).In some embodiments, the photoreactive amino acid analog may be a benzophenone-based unnatural amino acid. Benzophenone-based unnatural amino acids can be easily prepared and are further beneficial due to their inertness to solvents. Upon irradiation with light having a wavelength of 350- 365 nm, benzophenone-based unnatural amino acids generate a reactive diradical intermediate, containing reactive triplet carbonyl states. The reactive diradical intermediate can covalently bind to a nearby nucleobase through C-H insertion. Benzophenone-based unnatural amino acids are activated with light of a longer wavelength, reducing the risk of damage to biomolecules; however, irradiation times are longer, risking the potential for non-specific interactions.In some embodiments, the photoreactive amino acid analog may be a diazirene-based unnatural amino acid. Upon irradiation with light having a wavelength of 350-380 nm, diazirine-based unnatural amino acids generate a reactive carbene intermediate. The reactive carbene intermediates rapidly form a covalent bond with a nearby nucleobase through C-C, C-H, O-H, or X-H (X = heteroatom) insertions. The reactive carbene intermediate can react with all nucleobases, including adenine, cytosine, guanine, thymine, and uracil, forming a covalent attachment with a nearby nucleobase. One example of an alkyl diazirene-based amino acid is a pyrrolysine analog that bears an alkyl diazirene reactive group attached by a short, flexible C2 linker (see, e.g., Dziuba et al. ChemBioChem 2020, 21, 88-93, which is hereby incorporated by reference in its entirety).In some embodiments, the photoreactive amino acid analog may beyl)ethoxy]carbonyl-lysine )ethoxy]carbonyl-lysine is genetically encodable and can beirradiated with red light to covalently bind the amino acid to a nearby nucleobase (see, e.g., Moritz et al. Angew. Chem. 2013, 52, 4690-4693, , which is hereby incorporated by reference in its entirety).Complexation of Circular Polyribonucleotide with a Targeting MoietyThe disclosure also provides circular polyribonucleotide that are complexed with (e.g., hybridized or bound to) one or more moieties that specifically bind a region of the circular polyribonucleotide, wherein each of the one or more moieties that specifically bind a region of the circular polyribonucleotide is conjugated to (e.g., directly, chemically-covalently conjugated) to one or more targeting moieties. In some embodiments, the moieties that specifically bind a region of the circular polyribonucleotide are the same moiety that specifically binds a region of the circular polyribonucleotide. In some embodiments, the moieties that specifically bind a region of the circular polyribonucleotide are different from one another. For example, the moieties that specifically bind to the region of the circular polyribonucleotide may be one or more polypeptide binding moieties and one or more oligonucleotide binding moieties. In some embodiments, the moieties that specifically bind to the region of the circular polyribonucleotide may be two or more polypeptide binding moieties that are different polypeptides from one another. The moietiesthat specifically bind to the region of the circular polyribonucleotide may be one or more oligonucleotide binding moieties that have different sequences from one another.The disclosure also provides circular polyribonucleotide complexed with (e.g., hybridized or hybridized and covalently attached to) a moiety that specifically binds a region of the circular polyribonucleotide. The moiety that specifically binds a region of the circular polyribonucleotide includes one or more photoreactive crosslinking agents. The binding moiety may be, for example, a polypeptide or an oligonucleotide. In some embodiments, the complex includes from 1 to 20 moieties (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, to 20) that each bind specifically to a region of the circular polyribonucleotide. In some embodiments, the moieties that specifically bind a region of the circular polyribonucleotide are the same moiety that specifically binds a region of the circular polyribonucleotide. In some embodiments, the moieties that specifically bind a region of the circular polyribonucleotide are different from one another. For example, the moieties that specifically bind to the region of the circular polyribonucleotide may be one or more polypeptide binding moieties and / or one or more oligonucleotide binding moieties. In some embodiments, the moieties that specifically bind to the region of the circular polyribonucleotide may be two or more polypeptide binding moieties that are different polypeptides from one another. The moieties that specifically bind to the region of the circular polyribonucleotide may be one or more oligonucleotide binding moieties that have different sequences from one another.Each moiety that specifically binds a region of the circular polyribonucleotide may also include a linker covalently connecting the moieties that specifically bind a region of the circular polyribonucleotide and the targeting moiety. The moiety that specifically binds a region of the circular polyribonucleotide may be, for example an oligonucleotide or a polypeptide.In some embodiments, the moiety binds a region of the circular polyribonucleotide that includes one or more of an IRES, a spacer sequence, or an expression sequence. In some embodiments, the moiety binds to one of the binding regions as shown in FIG. 2. In some embodiments, the moiety binds a region in an IRES. In some embodiments, the moiety does not bind a region in an IRES. In some embodiments, the moiety binds a region in a spacer sequence. In some embodiments, the moiety does not bind a region in a spacer sequence. In some embodiments, the moiety binds at least part of a spacer sequence. In some embodiments, the moiety binds at least part of two spacer sequences. In some embodiments, the moiety binds a region in a coding region. In some embodiments, the moiety does not bind a region in a coding region. In some embodiments, the moiety binds a region in a spacer sequence and / or a coding region but does not bind a region in an IRES. In some embodiments, the binding region is sufficiently distant in sequence and space from the expression sequence so that it does not interfere with or minimizes interference with translation efficiency. For example, the binding region may be from about 10 nucleotides to about 200 nucleotides (e.g., from about 10 nucleotides to 170 nucleotides, 10 nucleotides to 150 nucleotides, 10 nucleotides to 130 nucleotides, 10 nucleotides to 100 nucleotides, 10 nucleotides to 70 nucleotides, 10 nucleotides to 50 nucleotides, 10 nucleotides to 30 nucleotides, 30 nucleotides to 200 nucleotides, 50 nucleotides to 200 nucleotides, 70 nucleotides to 200 nucleotides, 100 nucleotides to 200 nucleotides, 130 nucleotides to 200 nucleotides, 150 nucleotides to 200 nucleotides, 170 nucleotides to 200 nucleotides, or 50 nucleotides to 100 nucleotides) from the 5’ or 3’ end of the expression sequence.Oligonucleotide Binding MoietiesIn some embodiments, the moiety that specifically binds a region of the circular polyribonucleotide an oligonucleotide. The oligonucleotide may be, for example, a ribonucleic acid, a deoxyribonucleic acid, a peptide nucleic acid, a locked nucleic acid, or a glycol nucleic acid.In some embodiments, each oligonucleotide is from about 10-500 nucleic acids in length (e.g., about 10-20, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-200, 10-300, 10-400, 20-50, 20-100, 20-200 20-300, 20-400, 30-50, 30-100, 30-200, 30-300, 30-400, 50-100, 50-200, 50-300, or 50- 400 ribonucleotides in length). In some embodiments, each oligonucleotide has at least 20% (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%) complementarity to a portion of the sequence of the circular polyribonucleotide. In some embodiments, each oligonucleotide has from 20% to 90% (e.g., from 20-90%, 20-90%, 20-90% 20-90%, 30%-90%, 40%-90%, or 50%-90% complementarity to a portion of the sequence of the circular polyribonucleotide. Each oligonucleotide may be DNA, RNA, a synthetic nucleic acid, or a hybrid. Each oligonucleotide may include one or more nucleic acid modifications as described herein.In some embodiments, the circular polyribonucleotide is hybridized to one, two, three, four, five, six, seven, eight, nine, ten or more oligonucleotides, each oligonucleotide being covalently conjugated to one or more targeting moieties. In some embodiments, the circular polyribonucleotide is hybridized to one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more oligonucleotides. In some embodiments, the circular polyribonucleotide is hybridized to 10, 20, 30, 40, or 50 or more oligonucleotides. In some embodiments, the circular polyribonucleotide is hybridized to 1-10, 2-10, 2-20, 2-50, 5-10, 5-20, 5-50, 10-20, 20-30, 30- 40, 40-50, 1-50, 20-50, 30-60 or 50-100 targeting moieties.In some embodiments, each oligonucleotide is hybridized to (e.g., shares at least partial complementarity sufficient for binding with) a sequence with a binding region of the circular polyribonucleotide. In some embodiments, wherein the circular polyribonucleotide includes either a coding region (e.g., including an expression sequence), the binding region is sufficiently distant in sequence and space from the coding region or target binding region so that it does not interfere with or minimizes interference with translation efficiency. In some embodiments, the binding region includes from 1 to 100 ribonucleotides (e.g., from 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, 10 to 100, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, or 90 to 100 ribonucleotides). For example, the binding region may include from 10 to 90 ribonucleotides (e.g., from 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20, 20 to 80, 30 to 80, 40 to 80, 50 to 80, 60 to 80, or 70 to 80 ribonucleotides). In some embodiments, the oligonucleotide has from 50% to 100% (e.g., from 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 70% to 100%, 80% to 100%, or 90% to 100%) complementarity to a portion of the binding region of the circular polyribonucleotide. For example, the oligonucleotide may have from 80% to 100% (e.g., from 85% to 100%, 90% to 100%, 95% to 100%, 80% to 95%, 80% to 90%, or 80% to 85%) and complementarity to a portion of the binding region of the circular polyribonucleotide.In some embodiments, the moiety that specifically binds a region of the circular polyribonucleotide and includes a photoreactive crosslinking agent is an oligonucleotide. The oligonucleotide may be, for example, a ribonucleic acid, a deoxyribonucleic acid, a peptide nucleic acid, a locked nucleic acid, or a glycol nucleic acid.In some embodiments, each oligonucleotide includes a photoreactive crosslinking agent. In some embodiments, the photoreactive crosslinking agent is attached to the 5’ end of the oligonucleotide. In some embodiments, the photoreactive crosslinking agent is attached to the 3’ end of the oligonucleotide. In some embodiments, the photoreactive crosslinking agent is a photoreactive nucleotide analog. In some embodiments, the photoreactive nucleotide analog replaces a single nucleotide within the oligonucleotide. In some embodiments, the photoreactive nucleotide analog is located at an internal position within the oligonucleotide. In some embodiments, the 3’ end of the oligonucleotide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the photoreactive nucleotide analog. In some embodiments, the 3’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 nucleotides (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 nucleotides) from the photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 nucleotides (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 nucleotides) from the photoreactive nucleotide analog.In some embodiments, each oligonucleotide includes one, two, three, four, five, six, seven, eight, nine, ten or more photoreactive crosslinking agents. In some embodiments, each photoreactive crosslinking agent is a photoreactive nucleotide analog. In some embodiments, each of the photoreactive nucleotide analogs replaces a single nucleotide within the oligonucleotide. In some embodiments, each photoreactive nucleotide analog is located at an internal position within the oligonucleotide. In some embodiments, the 3’ end of the oligonucleotide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nearest photoreactive nucleotide analog. In some embodiments, the 3’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 nucleotides (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 nucleotides) from the nearest photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nearest photoreactive nucleotide analog. In some embodiments, the 5’ end of the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 nucleotides (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 nucleotides) from the nearest photoreactive nucleotide analog. In some embodiments, at least one of the photoreactive crosslinking agents is attached to the 5’ end of the oligonucleotide. In some embodiments, at least one of the photoreactive crosslinking agents is attached to the 3’ end of the oligonucleotide. In some embodiments, the oligonucleotide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 nucleotides (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 nucleotides) between each of the photoreactive nucleotide analogs. For example, the oligonucleotide may have one photoreactive nucleotide analog attached to the 5’ end and a second photoreactive nucleotide analog 8 nucleotides away from the 5’ end. The oligonucleotide may have one photoreactive nucleotide analog attached to the 5’ end, a second photoreactive nucleotide analog 10 nucleotides away from the 5’ end, and a third photoreactive nucleotide analog 15 nucleotides away from the 3’ end and 8 nucleotides away from the second photoreactive nucleotide analog.In some embodiments, each oligonucleotide is from about 5-500 nucleotides in length (e.g., about 5-20, 5-30, 5-40, 5-50, 5-60, 5-70, 5-80, 5-90, 5-100, 5-200, 5-300, 5-400, 20-50, 20-100, 20-20020-300, 20-400, 30-50, 30-100, 30-200, 30-300, 30-400, 50-100, 50-200, 50-300, or 50-400 nucleotides in length).In some embodiments, each oligonucleotide has at least 20% (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, or 90%) complementarity to a portion of the sequence of the circular polyribonucleotide. In some embodiments, each oligonucleotide has from 20% to 90% (e.g., from 20-90%, 20-90%, 20-90% 20-90%, 30%-90%, 40%-90%, or 50%-90%) complementarity to a portion of the sequence of the circular polyribonucleotide. Each oligonucleotide may be DNA, RNA, a synthetic nucleic acid, or a hybrid. Each oligonucleotide may include one or more nucleic acid modifications as described herein.In some embodiments, the oligonucleotide includes an aptamer. In some embodiments, the aptamer specifically binds to the linker or targeting moiety.In some embodiments, the circular polyribonucleotide is annealed and covalently bound to one, two, three, four, five, six, seven, eight, nine, ten or more oligonucleotides, each oligonucleotide being covalently conjugated to one or more targeting moieties. In some embodiments, the circular polyribonucleotide is annealed and covalently bound to one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more oligonucleotides. In some embodiments, the circular polyribonucleotide is annealed and covalently bound to 10, 20, 30, 40, or 50 or more oligonucleotides. In some embodiments, the circular polyribonucleotide is annealed and covalently bound to 1-10, 2-10, 2-20, 2-50, 5-10, 5-20, 5-50, 10-20, 20-30, 30-40, 40-50, 1- 50, 20-50, 30-60 or 50-100 targeting moieties.In some embodiments, each oligonucleotide is annealed (e.g., shares at least partial complementarity sufficient for binding with) and covalently bound to (e.g., photo-crosslinked) a sequence with a binding region of the circular polyribonucleotide. In some embodiments, wherein the circular polyribonucleotide includes either a coding region (e.g., including an expression sequence), the binding region is sufficiently distant in sequence and space from the coding region or target binding region so that it does not interfere with or minimizes interference with translation efficiency. In some embodiments, the binding region includes from 1 to 100 ribonucleotides (e.g., from 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, 1 to 10, 10 to 100, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, or 90 to 100 ribonucleotides). For example, the binding region may include from 10 to 90 ribonucleotides (e.g., from 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20, 20 to 80, 30 to 80, 40 to 80, 50 to 80, 60 to 80, or 70 to 80 ribonucleotides). In some embodiments, the oligonucleotide has from 50% to 100% (e.g., from 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 100%, 70% to 100%, 80% to 100%, or 90% to 100%) complementarity to a portion of the binding region of the circular polyribonucleotide. For example, the oligonucleotide may have from 80% to 100% (e.g., from 85% to 100%, 90% to 100%, 95% to 100%, 80% to 95%, 80% to 90%, or 80% to 85%) and complementarity to a portion of the binding region of the circular polyribonucleotide. In some embodiments, the binding region has zero or one mismatch with the oligonucleotide.Polypeptide Binding MoietiesIn some embodiments, the moiety that specifically binds a region of the circular polyribonucleotide and a targeting moiety by way of a linker is polypeptide. In some embodiments, the circular polyribonucleotide is bound to at least one polypeptide, wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 1 to 50 polypeptides (e.g., from 1 to 40, 1 to 30, 1 to 20, 1 to 10, 1 to 5, 5 to 50, 10 to 50, 20 to 50, 30 to 50, or 40 to 50 polypeptides), wherein each polypeptide is complexed to at least one targeting moiety.The polypeptide may include an RNA binding protein domain. In some embodiments, the RNA binding protein domain (RBP) may a be an RNA recognition motif (RRM), K homology domain, a zinc finger motif, a Pumilio homology domain, pentatricopeptide repeat domain, pseudouridine synthase and archaeosine transglycosylase domain, a THUMP domain, a YT521-B homology domain, a double stranded RNA binding domain, a helicase domain, a cold shock domain, an S1 domain, an Sm domain, a La motif, a Piwi-Argonaute-Zwille domain, or an intrinsically disordered region.In some embodiments, the circular polyribonucleotide is bound to at least one polypeptide, wherein each polypeptide is complexed to at least one targeting moiety.In some embodiments, the moiety that specifically binds a region of the circular polyribonucleotide and includes one or more photoreactive crosslinking agents is a polypeptide. In some embodiments, the circular polyribonucleotide is bound to at least one polypeptide, wherein each polypeptide is complexed to at least one targeting moiety. In some embodiments, the circular polyribonucleotide is bound to from 1 to 50 polypeptides (e.g., from 1 to 40, 1 to 30, 1 to 20, 1 to 10, 1 to 5, 5 to 50, 10 to 50, 20 to 50, 30 to 50, or 40 to 50 polypeptides), wherein each polypeptide is complexed to at least one targeting moiety.In some embodiments, each polypeptide includes a photoreactive crosslinking agent. In some embodiments, the photoreactive crosslinking agent is attached to the N-terminus of the polypeptide. In some embodiments, the photoreactive crosslinking agent is attached to the C-terminus of the polypeptide. In some embodiments, the photoreactive crosslinking agent is a photoreactive amino acid analog. In some embodiments, the photoreactive amino acid analog replaces a single amino acid within the polypeptide. In some embodiments, the photoreactive amino acid analog is located at an internal position within the polypeptide. In some embodiments, the C-terminus of the polypeptide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, or 8 amino acids from the photoreactive amino acid analog. In some embodiments, the C-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 amino acids (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 amino acids) from the photoreactive amino acid analog. In some embodiments, the N-terminus of the polypeptide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, or 8 amino acids from the photoreactive amino acid analog. In some embodiments, the N-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 amino acids (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 amino acids) from the photoreactive amino acid analog.In some embodiments, each polypeptide includes one, two, three, four, five, six, seven, eight, nine, ten or more photoreactive crosslinking agents. In some embodiments, each photoreactive crosslinking agent is a photoreactive amino acid analog. In some embodiments, each of the photoreactive amino acid analogs replaces a single amino acid within the polypeptide. In some embodiments, each photoreactive amino acid analog is located at an internal position within the polypeptide. In some embodiments, the C-terminus of the polypeptide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, or 8 amino acids from the nearest photoreactive amino acid analog. In some embodiments, the C-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 amino acids (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 amino acids) from the nearest photoreactive amino acid analog. In some embodiments, the N-terminus of the polypeptide has at least 1 , e.g., at least 1 , 2, 3, 4, 5, 6, 7, or 8 amino acids from the nearest photoreactive amino acid analog. In some embodiments, the N-terminus of the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 aminoacids (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 amino acids) from the nearest photoreactive amino acid analog. In some embodiments, at least one of the photoreactive crosslinking agents is attached to the N-terminus of the polypeptide. In some embodiments, at least one of the photoreactive crosslinking agents is attached to the C-terminus of the polypeptide. In some embodiments, the polypeptide has from 1 to 50, e.g., 2 to 50, e.g., 8 to 50 amino acids (e.g., 8 to 10, 8 to 15, 8 to 20, 8 to 25, 8 to 30, 8 to 35, 8 to 40, 8 to 45, 15 to 50, 20 to 40, or 30 to 35 amino acids) between each of the photoreactive amino acid analogs. For example, a polypeptide may have one photoreactive amino acid analog attached to the N-terminus and a second photoreactive amino acid analog 8 amino acids away from the N-terminus. The polypeptide may have one photoreactive amino acid analog attached to the N-terminus, a second photoreactive amino acid analog 10 amino acids away from the N-terminus, and a third photoreactive amino acid analog 15 amino acids away from the C- terminus and 8 amino acids away from the second photoreactive amino acid analog. In some embodiments, the RNA binding protein domain may be an RNA recognition motif. RRMs are the most common and well-studied RNA-binding domain. The Protein Data Bank includes over 500 known structures which have an RRM. RRMs average 90 amino acids in size and adopt a β1α1β2β3α2β4 topology forming two α helices against an antiparallel β sheet, which houses the conserved RNA-binding ribonucleoprotein 1 and ribonucleoprotein 2 motifs in the central β1 and β3 strands. In some embodiments, RRMs interact with from 2 to 8 nucleotides (e.g., 2, 3, 4, 5, 6, 7, and 8 nucleotides) in single-stranded RNA commonly. This interaction may occur through several sequential stacking interactions and hydrogen bonds with ribonucleoprotein motifs, often with nanomolar affinities. Each RRM may have its own sequence preferences, often for degenerate sequences such as GU-rich tracts. In some embodiments, the RBP includes multiple ribonucleoprotein motifs. The combination of consecutive ribonucleoprotein motifs in an RBP dramatically increases binding affinity and specificity. In some embodiments, the polypeptide has a K homology domain. The K homology (KH) domain was first discovered in heterogeneous nuclear ribonucleoprotein K (hnRNPK). The KH domain includes about 70 amino acid residues, and typically recognizes about 4 nucleotides in single stranded RNA. KH domains may adopt either a type I β1α1α2β2β′α′ topology, in eukaryotes, or the reverse type II α′β′β1α1α2β2 topology, in prokaryotes, with a conserved “GXXG” RNA-binding motif (SEQ ID NO: 56) located between the α1 and α2 helices. RNA binding may occur in a hydrophobic pocket of the KH domain and may include several hydrogen bonds coordinated by the “GXXG” motif (SEQ ID NO: 56). Proteins having a KH domain and RNA have few stacking interactions. Furthermore, proteins having a KH domain usually have weak micromolar RNA affinities. Multiple KH domains in an RBP can independently or synergistically increase binding specificity. In some embodiments, the polypeptide includes a zinc finger motif. Zinc finger motifs may be found in a large family of proteins that average 30 amino acids in size and form a simple ββα topology in which residues in the β hairpin turn and α helix are coordinated by a Zn2+ ion. Zinc finger motif polypeptides may bind DNA but have been additionally shown to bind RNA. Zinc finger motifs include subtypes that interact with RNA and include amino acid sequences of CCHC (SEQ ID NO: 57), CCCH (SEQ ID NO: 58), CCCC (SEQ ID NO: 59), and CCHH (SEQ ID NO: 60) subtypes, where C and H refer to the interspersed cysteine and histidine residues that coordinate the zinc atom, respectively. The zinc finger motif subtypes display a range of sequence and structural specificities. The CCHC (SEQ ID NO: 57) subtype recognizes stem-loop elements in RNA through contacts with bases in the loop and thephosphate backbone of the stem. The CCCH (SEQ ID NO: 58) and CCCC (SEQ ID NO: 59) subtypes tend to recognize 3 nucleotide repeats through multiple such zinc finger motifs in one RBP. These contacts may be formed through hydrogen bonds with bases and the insertion of aromatic side chains that stack between bases. The versatile and abundant CCHH (SEQ ID NO: 60) subtype interact swith both single-stranded and double-stranded RNA. Thus, designer zinc finger motifs may be use for directed binding of RNA sequences. In some embodiments, the RNA binding protein includes a Pumilio homology domain. The Pumilio family of proteins occurs in most eukaryotes and is defined by the Pumilio homology domain. The Pumilio homology domain is very large, consisting of eight α-helical repeats of a highly conserved 36- amino acid sequence that forms a concave RNA-binding surface. Each repeat recognizes one unpaired RNA base through hydrogen bonds and a stabilizing stacking interaction, where the full domain recognizes up to 8 nucleotides in single-stranded RNA with low-nanomolar affinity. Wild-type Pumilio homology domain repeats do not specifically recognize cytosine; however, protein engineering has produced repeats that do. This protein engineering combined with the PUF domain’s predictable base recognition code allow modular design of Pumilio proteins that recognize from 8 nucleotides to 10- nucleotides sequences containing all RNA bases. In some embodiments, the polypeptide includes a pentatricopeptide repeat domain. Pentatricopeptide repeats include about 35 amino acid residues in length and form two antiparallel α helices.2–30 repeats form a solenoid-shaped scaffold that binds specific single-stranded RNA sequences with nanomolar affinity. Two residues in each repeat determine base-specific binding through hydrogen bonds, enabling the development of pentatricopeptide repeat domains designed to bind specified single-stranded RNA sequences. In some embodiments, the polypeptide includes a pseudouridine synthase and archaeosine transglycosylase (PUA) domain. PUA domains include a range from 67 to 94 amino acids residues (e.g., 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, and 94 amino acid residues), with a β1α1β2β3β4β5α2β6 architecture that forms a pseudobarrel encased by two α helices. PUA domains may contact double-stranded RNA, and its adjacent loops or overhangs through extensive hydrogen bonds may contact all parts of the RNA. These contacts are typically formed by a glycine-rich loop between α1 and β2 or α2 and β6. Unlike many other domains, PUA domains are not found as tandem repeats. In some embodiments, the polypeptide includes a THUMP domain. Named for thiouridine synthase, methyltransferase, and pseudouridine synthase, the THUMP domain is found in numerous tRNA-modifying enzymes. THUMP domains are always found in proximity to RNA-modifying domains and often in proximity to an N-terminal ferredoxin-like domain. THUMP domains include about 100 amino acids residues and display a α1α2β1α3β2β2 topology that forms parallel α helices flanking a β sheet. In some embodiments, the polypeptide includes a YT521-B homology (YTH) domain. The YTH domain is found in the YTH family of proteins that identify N6-methyladenosine (m6A) marks in RNA. The YTH domain ranges from 100 to 150 amino acids residues in length and forms a six-stranded β barrel surrounded by four or five α helices. Three residues in the hydrophobic core of the β barrel trap the methyl group of m6A in an aromatic cage consisting of hydrogen bonds with the adenosine and π interactions between tryptophan rings and the methyl group. The YTH domain specifically binds m6A over unmodified adenosines.In some embodiments, the polypeptide includes a double-stranded RNA binding domain or motif. The double-stranded RNA binding domain or motif may include from 65 to 70 amino acids residues. Double-stranded RNA binding domains specifically recognize and bind double-stranded RNA and are found in proteins with roles in viral protection, RNAi, and cellular transport. Double-stranded RNA binding domains often appear as tandem repeats or in combination with other functional RNA-binding domains, such as RNA-editing or helicase domains. The double-stranded RNA binding domain is made up of an α1β1β2β3α2 fold that forms an antiparallel β sheet flanked by α helices on one face. Double-stranded RNA binding domains specifically recognize the structure of an A-form RNA helix, spanning up to 16 base pairs with hydrogen-bond contacts to the phosphodiester backbone and 2′ OH. In some cases, double- stranded RNA binding domains have demonstrated base-specific contacts, such as to bases in adjacent loops. In some embodiments, the polypeptide includes a helicase domain. Helicase domains are found in all forms of life in helicase proteins, which unwind both DNA and double-stranded RNA. Helicases include six superfamilies, of which superfamily 1 and superfamily 2 contain all the eukaryotic RNA helicases. RNA-binding helicases include the Upf1-like family in superfamily 1 and the DEAD-box, DEAH, RIG-I-like, Ski2-like, and NS3 families in superfamily 2. The remaining superfamilies, 3–6, contain bacterial and viral helicases that form multimeric rings. Helicase domains are very large, containing 350– 400 amino acid residues. In superfamily 1 and superfamily 2, the helicase domain is composed of two “recombinase A (recA)-like” subdomains, each of which contains an ATP-catalytic core, a nucleic-acid- binding region, and subdomains that coordinate the two. Within families of helicases these subdomains are quite conserved. Helicase monomers in the ring-forming superfamilies of helicases are similarly quite large and composed of multiple subdomains. Bound RNA is surrounded by recA-like domains or, in the case of multimeric helicases, RNA is pulled through the center of the ring. Contacts with RNA are dominated by hydrogen bonds to phosphate and sugar moieties, but contacts with bases have only occasionally been observed. Affinities to RNA for proteins having a helicase domain are often in the nanomolar range, although they vary greatly by helicase and are modulated by other subdomains of the helicase. ATP binding generally promotes higher affinity to RNA by causing the helicase RNA-binding regions to clamp. In some embodiments, the polypeptide may include a cold shock domain. The cold shock domain is found in a large family of proteins associated with cold adaptation found in all domains of life. Cold shock domains are composed of about 70 amino acids residues or more and five antiparallel β strands that form a common β barrel structure known as an oligosaccharide / oligonucleotide-binding fold. Cold shock domains contain the conserved ribonucleoprotein 1 and ribonucleoprotein 2 motifs common to RNA recognition motifs, which bind single-stranded RNA. Cold shock domains contact 3 or 4 nucleotides through sequential stacking interactions and hydrogen bonds with bases, achieving nanomolar affinities. Cold shock domain containing proteins vary greatly in the types of sequences they recognize. In some embodiments, the polypeptide includes an S1 RNA-binding domain. The S1 domain includes about 70 amino acid residues, which form a 5-stranded antiparallel β barrel in the same oligonucleotide binding fold family as the cold shock domain. S1 domains are additionally found in several exoribonucleases and eukaryotic translation initiation factors and in combination with other RNA-binding domains such as the KH domain or cold shock domains. Despite their abundance, very little structuralinformation is available for S1 domains in complex with RNA. S1 domains interact with both single- stranded RNA and double-stranded RNA in the context of the RNA-binding channel of exoribonucleases.In some embodiments, the polypeptide includes a Sm-RNA binding motif. The Sm RNA-binding motif is found in Sm and like-Sm proteins in eukaryotes and archaea and in Hfq protein in prokaryotes. The Sm motif consists of about 70 residues with an a1 p1 p2p3p4p5 topology that forms a curved antiparallel p sheet. Sm-containing proteins readily multimerize through interactions between strands p4 and p5 in two Sm motifs. For example, Sm-Sm interactions link the seven human Sm proteins that make up the protein core of small nuclear ribonucleoproteins. The Sm multimers bind RNA with nanomolar affinity. Two Sm motifs form a 6-nucleotide binding surface that binds specific bases, often uridines, through hydrogen bonds and stacking interactions.In some embodiments, the polypeptide includes a La motif. La motif includes about 90 amino acid residues and is found in eukaryotic La and La-related proteins (LARPs). The La motif consists of five a helices and three p strands that form a small antiparallel p sheet against a modified winged-helix fold. The winged-helix structure itself is common to several other RNA-binding proteins. La motifs are always found adjacent to at least one RNA recognition motif, where the combination of these two domains likely evolved as a unit. In La proteins, the dual La motif and RNA recognition motif region tightly binds the UUU-OH elements at the 3' ends of polymerase-l Il-transcribed small RNAs. Binding occurs in a cleft between the La motif and the RNA recognition motif rather than the traditional RNA-binding surfaces of either the RNA recognition motif or the La motif winged-helix fold. Several uracil bases stack with highly conserved aromatic residues in the La motif, and hydrogen bonds from both the La motif and RNA- recognition motif coordinate bases, phosphates, and the terminating 2' OH. These contacts result in low- nanomolar affinities of the La motif for 3'-terminal UUU-OH elements.In some embodiments, the polypeptide includes a Piwi-Argonaute-Zwille or PIWI RNA-binding domains. These RNA binding domains define the Argonaute family of proteins found in eukaryotes. These domains are found on opposite sides of the Argonaute protein, both domains facilitate binding of small interfering RNA and microRNA guides to mRNA targets. The Piwi-Argonaute-Zwille domain occurs in Dicer proteins in addition to Argonaute proteins. Crystal structures of the Piwi-Argonaute-Zwille domain display a six-stranded p barrel topped with two a helices and flanked on the opposite side by a special appendage containing a p hairpin and short a helix. A binding pocket formed between this appendage and the p barrel binds the 2 nucleotide 3' overhang in guide RNAs with low-micromolar affinity. Binding is coordinated mostly by conserved tyrosine residues that form hydrogen bonds with the phosphate backbone and sugar hydroxyls of the two terminal nucleotides. The PIWI RNA-binding domain tertiary structure forms an RNase H-like fold consisting of a five-stranded p sheet flanked by a helices on both faces. The PIWI domain has endonucleolytic activity in some cases, but primarily stabilizes the gRNA- mRNA duplex seed region through hydrogen bonds with the gRNA backbone of nucleotides 3-5 and the 5' overhang base.In some embodiments, the polypeptide includes an intrinsically disordered region. Intrinsically disordered regions are unstructured and often consist of repeats of arginine / serine residues, arginine / glycine, arginine- or lysine-rich patches, or short linear motifs of amino acids. Despite their lack of structure, intrinsically disordered regions have been found to dominate the composition in over 20% of RNA binding proteins. Intrinsically disordered regions may be the sole RNA-binding domain in an RNA binding protein and may actually drive the majority of protein-RNA interactions in the cell. Like globularRNA-binding domains, intrinsically disordered regions are conserved, often occur multiple times in one RNA binding protein, and can coordinate RNA binding in concert with other domains. Intrinsically disordered regions have been shown to drive higher affinity to RNA in RNA binding proteins that contain ordered RNA-binding domains and can themselves transition to an ordered state once bound to RNA. Intrinsically disordered regions show little RNA sequence dependence, however, suggesting that these regions’ high affinity for RNA is predominantly driven by electrostatic attraction to the phosphodiester backbone.In some embodiments, the polypeptide may include another domain which allows for the protein to complex with the polyribonucleotide described herein.Circular PolyribonucleotidesThe disclosure provides circular polyribonucleotide that are complexed with one or more moieties that specifically bind a region of the circular polyribonucleotide, wherein each of the one or more moieties that specifically bind a region of the circular polyribonucleotide is conjugated to (e.g., directly, chemically- covalently conjugated) to one or more targeting moieties.Expression SequencesIn some embodiments, the circular polyribonucleotide includes at least one expression sequence (e.g., coding region) that encodes a polypeptide. In some embodiments, the polypeptide, when expressed in the cell is functional. In some embodiments, the moiety that specifically bind a region of the circular polyribonucleotide binds a region of the circular polyribonucleotide includes or more expression sequences.The encoded polypeptide may have a length from about 5 to about 40,000 amino acids, about 15 to about 35,000 amino acids, about 20 to about 30,000 amino acids, about 25 to about 25,000 amino acids, about 50 to about 20,000 amino acids, about 100 to about 15,000 amino acids, about 200 to about 10,000 amino acids, about 500 to about 5,000 amino acids, about 1 ,000 to about 2,500 amino acids, or any range therebetween. In some embodiments, the polypeptide has a length of less than about 40,000 amino acids, less than about 35,000 amino acids, less than about 30,000 amino acids, less than about 25,000 amino acids, less than about 20,000 amino acids, less than about 15,000 amino acids, less than about 10,000 amino acids, less than about 9,000 amino acids, less than about 8,000 amino acids, less than about 7,000 amino acids, less than about 6,000 amino acids, less than about 5,000 amino acids, less than about 4,000 amino acids, less than about 3,000 amino acids, less than about 2,500 amino acids, less than about 2,000 amino acids, less than about 1 ,500 amino acids, less than about 1 ,000 amino acids, less than about 900 amino acids, less than about 800 amino acids, less than about 700 amino acids, less than about 600 amino acids, less than about 500 amino acids, less than about 400 amino acids, less than about 300 amino acids, or less may be useful.Some examples of a polypeptides include a fluorescent tag or marker, an antigen, a peptide therapeutic, a synthetic or analog peptide from a naturally-bioactive peptide, an agonist or antagonist peptide, an anti-microbial peptide, a pore-forming peptide, a bicyclic peptide, a targeting or cytotoxic peptide, a degradation or self-destruction peptide, and degradation or self-destruction peptides. Peptides useful in the invention described herein also include antigen-binding peptides, e.g., antigen binding antibody or antibody-like fragments, such as single chain antibodies, nanobodies (see, e.g., Steeland etal. 2016. Nanobodies as therapeutics: big opportunities for small antibodies. Drug Discov Today: 21 (7): 1076-113). Such antigen binding peptides may bind a cytosolic antigen, a nuclear antigen, an intra- organellar antigen.The polypeptide may be produced in substantial amounts. As such, the polypeptide may be any proteinaceous molecule that can be produced. A polypeptide can be a polypeptide that can be secreted from a cell, or localized to the cytoplasm, nucleus or membrane compartment of a cell. Some polypeptides include, but are not limited to, at least a portion of a viral envelope protein, metabolic regulatory enzymes (e.g., that regulate lipid or steroid production), an antigen, a toleragen, a cytokine, a toxin, enzymes whose absence is associated with a disease, and polypeptides that are not active in an animal until cleaved (e.g., in the gut of an animal), and a hormone.In some embodiments, the circular polyribonucleotide includes an expression sequence encoding a protein e.g., a therapeutic protein. In some embodiments, therapeutic proteins that can be expressed from the circular polyribonucleotide disclosed herein have antioxidant activity, binding, cargo receptor activity, catalytic activity, molecular carrier activity, molecular function regulator, molecular transducer activity, nutrient reservoir activity, protein tag, structural molecule activity, toxin activity, transcription regulator activity, translation regulator activity, or transporter activity. Some examples of therapeutic proteins may include, but are not limited to, an enzyme replacement protein, a protein for supplementation, a protein vaccination, antigens (e.g. tumor antigens, viral, bacterial), hormones, cytokines, antibodies, immunotherapy (e.g. cancer), cellular reprogramming / transdifferentiation factor, transcription factors, chimeric antigen receptor, transposase or nuclease, immune effector (e.g., influences susceptibility to an immune response / signal), a regulated death effector protein (e.g., an inducer of apoptosis or necrosis), a non-lytic inhibitor of a tumor (e.g., an inhibitor of an oncoprotein), an epigenetic modifying agent, epigenetic enzyme, a transcription factor, a DNA or protein modification enzyme, a DNA-intercalating agent, an efflux pump inhibitor, a nuclear receptor activator or inhibitor, a proteasome inhibitor, a competitive inhibitor for an enzyme, a protein synthesis effector or inhibitor, a nuclease, a protein fragment or domain, a ligand or a receptor, and a CRISPR system or component thereof.In some embodiments, exemplary proteins that can be expressed from the circular polyribonucleotide disclosed herein include human proteins, for instance, receptor binding protein, hormone, growth factor, growth factor receptor modulator, and regenerative protein (e.g., proteins implicated in proliferation and differentiation, e.g., therapeutic protein, for wound healing). In some embodiments, exemplary proteins that can be expressed from the circular polyribonucleotide disclosed herein include EGF (epithelial growth factor). In some embodiments, exemplary proteins that can be expressed from the circular polyribonucleotide disclosed herein include enzymes, for instance, oxidoreductase enzymes, metabolic enzymes, mitochondrial enzymes, oxygenases, dehydrogenases, ATP-independent enzyme, and desaturases. In some embodiments, exemplary proteins that can be expressed from the circular polyribonucleotide disclosed herein include an intracellular protein or cytosolic protein. In some embodiments, the circular polyribonucleotide expresses a NanoLuc® luciferase (nLuc). In some embodiments, exemplary proteins that can be expressed from the circular polyribonucleotide disclosed herein include a secretary protein, for instance, a secretary enzyme. In some cases, the circular polyribonucleotide expresses a secretary protein that can have a short half-life therapeutic in the blood, or can be a protein with a subcellular localization signal, or protein with secretory signal peptide. In someembodiments, the circular polyribonucleotide expresses a Gaussia Luciferase (gLuc). In some cases, the circular polyribonucleotide expresses a non-human protein, for instance, a fluorescent protein, an energy- transfer acceptor, or a protein-tag like Flag, Myc, or His. In some embodiments, exemplary proteins that can be expressed from the circular polyribonucleotide include a GFP. In some embodiments, the circular polyribonucleotide expresses tagged proteins, .e.g., fusion proteins or engineered proteins containing a protein tag, e.g., chitin binding protein (CBP), maltose binding protein (MBP), Fc tag, glutathione-S- transferase (GST), AviTag, Calmodulin-tag, polyglutamate tag; E-tag, FLAG-tag), HA-tag, His-tag, Myc- tag, NE-tag, S-tag, SBP-tag, Softag 1 , Softag 3, Spot-tag, Strep-tag; TC tag, Ty tag, V5 tag ; VSV-tag; or Xpress tag.In some embodiments, the circular polyribonucleotide encodes the expression of an antibody, e.g., an antibody fragment, or a portion thereof. In some embodiments, the antibody expressed by the circular polyribonucleotide can be of any isotype, such as IgA, IgD, IgE, IgG, or IgM. In some embodiments, the circular polyribonucleotide expresses a portion of an antibody, such as a light chain, a heavy chain, a Fc fragment, a CDR (complementary determining region), a Fv fragment, or a Fab fragment, a further portion thereof. In some embodiments, the circular polyribonucleotide expresses one or more portions of an antibody. For instance, the circular polyribonucleotide can include more than one expression sequence, each of which expresses a portion of an antibody, and the sum of which can constitute the antibody. In some cases, the circular polyribonucleotide includes one expression sequence coding for the heavy chain of an antibody, and another expression sequence coding for the light chain of the antibody. In some cases, when the circular polyribonucleotide is expressed in a cell or a cell-free environment, the light chain and heavy chain can be subject to appropriate modification, folding, or other post-translation modification to form a functional antibody.Regulatory ElementsIn some embodiments, the polyribonucleotide described herein (e.g., the polyribonucleotide cargo of the polyribonucleotide) includes one or more regulatory elements. In some embodiments, the polyribonucleotide includes a regulatory element, e.g., a sequence that modifies expression of an expression sequence within the polyribonucleotide.A regulatory element may include a sequence that is located adjacent to an expression sequence that encodes an expression product. A regulatory element may be linked operatively to the adjacent sequence. A regulatory element may increase an amount of product expressed as compared to an amount of the expressed product when no regulatory element exists. In addition, one regulatory element can increase amounts of products expressed for multiple expression sequences attached in tandem. Hence, one regulatory element can enhance the expression of one or more expression sequences. Multiple regulatory elements are well-known to persons of ordinary skill in the art.In some embodiments, the regulatory element is a translation modulator. A translation modulator can modulate translation of the expression sequence in the polyribonucleotide. A translation modulator can be a translation enhancer or suppressor. In some embodiments, the polyribonucleotide includes at least one translation modulator adjacent to at least one expression sequence. In some embodiments, the polyribonucleotide includes a translation modulator adjacent each expression sequence. In some embodiments, the translation modulator is present on one or both sides of each expression sequence, leading to separation of the expression products, e.g., peptide(s) and or polypeptide (s).In some embodiments, the regulatory element is a microRNA (miRNA) or a miRNA binding site. Further examples of regulatory elements are described, e.g., in paragraphs

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[0161] of International Patent Publication No. WO2019 / 118919, which is hereby incorporated by reference in its entirety.Internal Ribosomal Entry SitesIn some embodiments, the polyribonucleotide described herein (e.g., the polyribonucleotide cargo of the polyribonucleotide) includes one or more internal ribosome entry site (IRES) elements. In some embodiments, the IRES is operably linked to one or more expression sequences (e.g., each IRES is operably linked to one or more expression sequences). In embodiments, the IRES is located between a heterologous promoter and the 5’ end of a coding sequence. In some embodiments, the moiety that specifically bind a region of the circular polyribonucleotide binds a region of the circular polyribonucleotide includes an IRES.A suitable IRES element to include in a polyribonucleotide includes an RNA sequence capable of engaging a eukaryotic ribosome. In some embodiments, the IRES element is at least about 5 nt, at least about 8 nt, at least about 9 nt, at least about 10 nt, at least about 15 nt, at least about 20 nt, at least about 25 nt, at least about 30 nt, at least about 40 nt, at least about 50 nt, at least about 100 nt, at least about 200 nt, at least about 250 nt, at least about 350 nt, or at least about 500 nt.In some embodiments, the IRES element is derived from the DNA of an organism including, but not limited to, a virus, a mammal, or a Drosophila. Such viral DNA may be derived from, but is not limited to, picomavirus complementary DNA (cDNA), with encephalomyocarditis virus (EMCV) cDNA and poliovirus cDNA. In one embodiment, Drosophila DNA from which an IRES element is derived includes, but is not limited to, an Antennapedia gene from Drosophila melanogaster.In some embodiments, if present, the IRES sequence is an IRES sequence of Taura syndrome virus, Triatoma virus, Theiler's encephalomyelitis virus, simian Virus 40, Solenopsis invicta virus 1 , Rhopalosiphum padi virus, Reticuloendotheliosis virus, fuman poliovirus 1 , Plautia stall intestine virus, Kashmir bee virus, Human rhinovirus 2, Homalodisca coagulata virus- 1 , Human Immunodeficiency Virus type 1 , Homalodisca coagulata virus- 1 , Himetobi P virus, Hepatitis C virus, Hepatitis A virus, Hepatitis GB virus, foot and mouth disease virus, Human enterovirus 71 , Equine rhinitis virus, Ectropis obliqua picorna-like virus, Encephalomyocarditis virus (EMCV), Drosophila C Virus, Crucifer tobamo virus, Cricket paralysis virus, Bovine viral diarrhea virus 1 , Black Queen Cell Virus, Aphid lethal paralysis virus, Avian encephalomyelitis virus, Acute bee paralysis virus, Hibiscus chlorotic ringspot virus, Classical swine fever virus, Human FGF2, Human SFTPA1 , Human AML1 / RUNX1 , Drosophila antennapedia, Human AQP4, Human AT1 R, Human BAG-I, Human BCL2, Human BiP, Human c-IAPI , Human c-myc, Human elF4G, Mouse NDST4L, Human LEF1 , Mouse HIF1 alpha, Human n.myc, Mouse Gtx, Human p27kipl, Human PDGF2 / c-sis, Human p53, Human Pim-I, Mouse Rbm3, Drosophila reaper, Canine Scamper, Drosophila Ubx, Human UNR, Mouse UtrA, Human VEGF-A, Human XIAP, Salivirus, Cosavirus, Parechovirus, Drosophila hairless, S. cerevisiae TFIID, S. cerevisiae YAP1 , Human c-src, Human FGF-I, Simian picomavirus, Turnip crinkle virus, Aichivirus, Crohivirus, Echovirus 11 , an aptamer to elF4G, Coxsackievirus B3 (CVB3) or Coxsackievirus A (CVB1 / 2). In yet another embodiment, the IRES is an IRES sequence of Coxsackievirus B3 (CVB3). In a further embodiment, the IRES is an IRES sequence of Encephalomyocarditis virus. In a further embodiment, the IRES is an IRES sequence of Theiler'sencephalomyelitis virus. In some embodiments, the IRES sequence has more than 90% sequence identify with one of the foregoing IRES sequences.The IRES sequence may have the sequence of wild-type CVB3 IRES sequence having the nucleic acid sequence of:GCAAA (SEQ ID NO: 96).The IRES sequence may be a CVB3 IRES sequence having the nucleic acid sequence of :GCAA (SEQ ID NO: 97).The IRES sequence may have a modified sequence in comparison to the wild-type IRES sequence. In some embodiments, when the last nucleotide of the wild-type IRES is not a cytosine nucleic acid residue, the last nucleotide of the wild-type IRES sequence may be modified such that it is a cytosine residue. For example, the IRES sequence may be a CVB3 IRES sequence wherein the terminal adenosine residue is modified to cytosine residue. In some embodiments, the modified CVB3 IRES may have the nucleic acid sequence of:GCAAC (SEQ ID NO: 98).In some embodiments, the IRES sequence is an encephalomyocarditis virus (EMCV) IRES. In some embodiments, the ECMV IRES may have the nucleic acid sequence of:( )In some embodiments, the IRES sequence is an Enterovirus 71 (EV71) IRES. In some embodiments, the IRES sequence is a wild-type EV71 sequence having the nucleic acid sequence of:AAGCG (SEQ ID NO: 100).In some embodiments, the terminal guanosine residue of the EV71 IRES sequence is modified to a cytosine residue. In some embodiments, the modified EV71 IRES may have the nucleic acid sequence of:AAGCC (SEQ ID NO: 101).In some embodiments, the polyribonucleotide includes at least one IRES flanking at least one (e.g., 2, 3, 4, 5 or more) expression sequence. In some embodiments, the IRES flanks both sides of at least one (e.g., 2, 3, 4, 5 or more) expression sequence. In some embodiments, the polyribonucleotide includes one or more IRES sequences on one or both sides of each expression sequence, leading to separation of the resulting peptide(s) and or polypeptide(s).In some embodiments, a polyribonucleotide described herein includes an IRES (e.g., an IRES operably linked to a coding region). For example, the polyribonucleotide may include any IRES as described in Fan et al. Nature Communications 13(1):3751 -3765, 2022 doi: 10.1038 / s41467-022-31327- y; Chen et al. Nature Biotechnology 41 :262-272, 2023; Chen et al. Mol. Cell 81 (20):4300-4318, 2021 ; Jopling et al. Oncogene 20:2664-2670, 2001 ; Baranick et al. PNAS 105(12):4733-4738, 2008; Lang et al. Molecular Biology of the Cell 13(5):1792-1801 , 2002; Dorokhov et al. PNAS 99(8):5301-5306, 2002; Wang et al. Nucleic Acids Research 33(7):2248-2258, 2005; Petz et a. Nucleic Acids Research 35(8):2473-2482, 2007; Chen et al. Science 268:415-417, 1995; and International Publication No. W02020 / 198403; International Patent Publication No. WO 2021 / 263124 A2; and International Publication No. WO2022 / 271965, each of which is hereby incorporated by reference in their entirety.Signal SequencesIn some embodiments, a polypeptide expressed from a circular polyribonucleotide disclosed herein includes a secreted protein, for example, a protein that naturally includes a signal sequence, or one that does not usually encode a signal sequence but is modified to contain one. In some embodiments, the polypeptide encoded by the circular polyribonucleotide includes a secretion signal. For example, the secretion signal may be the naturally encoded secretion signal for a secreted protein. In another example, the secretion signal may be a modified secretion signal for a secreted protein. In other embodiments, the polypeptide encoded by the circular polyribonucleotide does not include a secretion signal.In some embodiments, a circular polyribonucleotide encodes multiple copies of the same polypeptide (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or more). In some embodiments, at least one copy of the polypeptide includes a signal sequence and at least one copy of the polypeptide does not include a signal sequence. In some embodiments, a circular polyribonucleotide encodes plurality of polypeptides (e.g., a plurality of different polypeptides or a plurality of polypeptides having less than 100% sequence identity), where at least one of the plurality of polypeptides includes a signal sequence and at least one copy of the plurality of polypeptides does not include a signal sequence.In some embodiments, the signal sequence is a wild-type signal sequence that is present on the N-terminus of the corresponding wild-type polypeptide, e.g., when expressed endogenously. In some embodiments, the signal sequence is heterologous to the polypeptide, e.g., is not present when the wild- type polypeptide is expressed endogenously. A polyribonucleotide sequence encoding a polypeptide may be modified to remove the nucleotide sequence encoding a wild-type signal sequence and / or add a sequence encoding a heterologous signal sequence.A polypeptide encoded by a polyribonucleotide may include a signal sequence that directs the polypeptide to the secretory pathway. In some embodiments, the signal sequence may direct the polypeptide to reside in certain organelles (e.g., the endoplasmic reticulum, Golgi apparatus, or endosomes). In some embodiments, the signal sequence directs the polypeptide to be secreted from the cell. For secreted proteins, the signal sequence may be cleaved after secretion, resulting in a mature protein. In other embodiments, the signal sequence may become embedded in the membrane of the cell or certain organelles, creating a transmembrane segment that anchors the protein to the membrane of the cell, endoplasmic reticulum, or Golgi apparatus. In certain embodiments, the signal sequence of a transmembrane protein is a short sequence at the N-terminal of the polypeptide. In other embodiments, the first transmembrane domain acts as the first signal sequence, which targets the protein to the membrane.In some embodiments, a polypeptide encoded by a polyribonucleotide includes either a secretion signal sequence, a transmembrane insertion signal sequence, or does not include a signal sequence.Cleavage DomainsA circular polyribonucleotide of the disclosure can include a cleavage domain (e.g., a stagger element or a cleavage sequence).The term “stagger element” refers to a moiety, such as a nucleotide sequence, that induces ribosomal pausing during translation. In some embodiments, the stagger element is a non-conserved sequence of amino-acids with a strong alpha-helical propensity followed by the consensus sequence - D(V / l)ExNPGP, where x= any amino acid (SEQ ID NO: 61). In some embodiments, the stagger element may include a chemical moiety, such as glycerol, a non-nucleic acid linking moiety, a chemical modification, a modified nucleic acid, or any combination thereof.In some embodiments, the circular polyribonucleotide includes at least one stagger element adjacent to an expression sequence. In some embodiments, the circular polyribonucleotide includes a stagger element adjacent to each expression sequence. In some embodiments, the stagger element is present on one or both sides of each expression sequence, leading to separation of the expression products, e.g., peptide(s) and or polypeptide(s). In some embodiments, the stagger element is a portion of the one or more expression sequences. In some embodiments, the circular polyribonucleotide includes one or more expression sequences, and each of the one or more expression sequences is separated from a succeeding expression sequence by a stagger element on the circular polyribonucleotide. In some embodiments, the stagger element prevents generation of a single polypeptide (a) from two rounds of translation of a single expression sequence or (b) from one or more rounds of translation of two or more expression sequences. In some embodiments, the stagger element is a sequence separate from the one or more expression sequences. In some embodiments, the stagger element includes a portion of an expression sequence of the one or more expression sequences.In some embodiments, the circular polyribonucleotide includes a stagger element. To avoid production of a continuous expression product, e.g., peptide or polypeptide, while maintaining rolling circle translation, a stagger element may be included to induce ribosomal pausing during translation. In some embodiments, the stagger element is at 3’ end of at least one of the one or more expression sequences. The stagger element can be configured to stall a ribosome during rolling circle translation of the circular polyribonucleotide. The stagger element may include, but is not limited to a 2A-like, orCHYSEL (SEQ ID NO: 62) (cis-acting hydrolase element) sequence. In some embodiments, the stagger element encodes a sequence with a C-terminal consensus sequence that is X1X2X3EX5NPGP (SEQ ID NO: 63), where X1 is absent or G or H, X2is absent or D or G, X3is D or V or I or S or M, and X5is any amino acid. In some embodiments, this sequence includes a non-conserved sequence of amino-acids with a strong alpha-helical propensity followed by the consensus sequence -D(V / I)EXNPGP (SEQ ID NO: 64), where x= any amino acid. Some nonlimiting examples of stagger elements includes GDVESNPGP (SEQ ID NO: 65), GDIEENPGP (SEQ ID NO: 66), VEPNPGP (SEQ ID NO: 67), IETNPGP (SEQ ID NO: 68), GDIESNPGP (SEQ ID NO: 69), GDVELNPGP (SEQ ID NO: 70), GDIETNPGP (SEQ ID NO: 71), GDVENPGP (SEQ ID NO: 72), GDVEENPGP (SEQ ID NO: 73), GDVEQNPGP (SEQ ID NO: 74), IESNPGP (SEQ ID NO: 75), GDIELNPGP (SEQ ID NO: 76), HDIETNPGP (SEQ ID NO: 77), HDVETNPGP (SEQ ID NO: 78), HDVEMNPGP (SEQ ID NO: 79), GDMESNPGP (SEQ ID NO: 80), GDVETNPGP (SEQ ID NO: 81), GDIEQNPGP (SEQ ID NO: 82), and DSEFNPGP (SEQ ID NO: 83). In some embodiments, the stagger element described herein cleaves an expression product, such as between G and P of the consensus sequence described herein. As one non-limiting example, the circular polyribonucleotide includes at least one stagger element to cleave the expression product. In some embodiments, the circular polyribonucleotide includes a stagger element adjacent to at least one expression sequence. In some embodiments, the circular polyribonucleotide includes a stagger element after each expression sequence. In some embodiments, the circular polyribonucleotide includes a stagger element is present on one or both sides of each expression sequence, leading to translation of individual peptide(s) and or polypeptide(s) from each expression sequence. In some embodiments, a stagger element includes one or more modified nucleotides or unnatural nucleotides that induce ribosomal pausing during translation. Unnatural nucleotides may include peptide nucleic acid (PNA), Morpholino and locked nucleic acid (LNA), as well as glycol nucleic acid (GNA) and threose nucleic acid (TNA). Examples such as these are distinguished from naturally occurring DNA or RNA by changes to the backbone of the molecule. Exemplary modifications can include any modification to the sugar, the nucleobase, the internucleoside linkage (e.g., to a linking phosphate / to a phosphodiester linkage / to the phosphodiester backbone), and any combination thereof that can induce ribosomal pausing during translation. Some of the exemplary modifications provided herein are described elsewhere herein. In some embodiments, the stagger element is present in the circular polyribonucleotide in other forms. For example, in some exemplary circular polyribonucleotides, a stagger element includes a termination element of a first expression sequence in the circular polyribonucleotide, and a nucleotide spacer sequence that separates the termination element from a first translation initiation sequence of an expression succeeding the first expression sequence. In some examples, the first stagger element of the first expression sequence is upstream of (5’ to) a first translation initiation sequence of the expression succeeding the first expression sequence in the circular polyribonucleotide. In some cases, the first expression sequence and the expression sequence succeeding the first expression sequence are two separate expression sequences in the circular polyribonucleotide. The distance between the first stagger element and the first translation initiation sequence can enable continuous translation of the first expression sequence and its succeeding expression sequence. In some embodiments, the first stagger element includes a termination element and separates an expression product of the first expression sequence from an expression product of its succeedingexpression sequences, thereby creating discrete expression products. In some cases, the circular polyribonucleotide including the first stagger element upstream of the first translation initiation sequence of the succeeding sequence in the circular polyribonucleotide is continuously translated, while a corresponding circular polyribonucleotide including a stagger element of a second expression sequence that is upstream of a second translation initiation sequence of an expression sequence succeeding the second expression sequence is not continuously translated. In some cases, there is only one expression sequence in the circular polyribonucleotide, and the first expression sequence and its succeeding expression sequence are the same expression sequence. In some exemplary circular polyribonucleotides, a stagger element includes a first termination element of a first expression sequence in the circular polyribonucleotide, and a nucleotide spacer sequence that separates the termination element from a downstream translation initiation sequence. In some such examples, the first stagger element is upstream of (5’ to) a first translation initiation sequence of the first expression sequence in the circular polyribonucleotide. In some cases, the distance between the first stagger element and the first translation initiation sequence enables continuous translation of the first expression sequence and any succeeding expression sequences.In some embodiments, the first stagger element separates one round expression product of the first expression sequence from the next round expression product of the first expression sequences, thereby creating discrete expression products. In some cases, the circular polyribonucleotide including the first stagger element upstream of the first translation initiation sequence of the first expression sequence in the circular polyribonucleotide is continuously translated, while a corresponding circular polyribonucleotide including a stagger element upstream of a second translation initiation sequence of a second expression sequence in the corresponding circular polyribonucleotide is not continuously translated. In some cases, the distance between the second stagger element and the second translation initiation sequence is at least 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x greater in the corresponding circular polyribonucleotide than a distance between the first stagger element and the first translation initiation in the circular polyribonucleotide. In some cases, the distance between the first stagger element and the first translation initiation is at least 2 nt, 3 nt, 4 nt, 5 nt, 6 nt, 7 nt, 8 nt, 9 nt, 10 nt, 11 nt, 12 nt, 13 nt, 14 nt, 15 nt, 16 nt, 17 nt, 18 nt, 19 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, 60 nt, 65 nt, 70 nt, 75 nt, or greater. In some embodiments, the distance between the second stagger element and the second translation initiation is at least 2 nt, 3 nt, 4 nt, 5 nt, 6 nt, 7 nt, 8 nt, 9 nt, 10 nt, 11 nt, 12 nt, 13 nt, 14 nt, 15 nt, 16 nt, 17 nt, 18 nt, 19 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, 60 nt, 65 nt, 70 nt, 75 nt, or greater than the distance between the first stagger element and the first translation initiation. In some embodiments, the circular polyribonucleotide includes more than one expression sequence.Examples of stagger elements are described in paragraphs

[0172] -

[0175] of International Patent Publication No. WO2019 / 118919, which is hereby incorporated by reference in its entirety.In some embodiments, a plurality of polypeptides encoded by a circular ribonucleotide may be separated by an IRES between each polypeptide (e.g., each polypeptide is operably linked to a separate IRES). For example, a circular polyribonucleotide may include a first IRES operably linked to a first expression sequence and a second IRES operably linked to a second expression sequence. The IRES may be the same IRES between all polypeptides. The IRES may be different between different polypeptides.In some embodiments, the plurality of polypeptides may be separated by a 2A self-cleaving peptide. For example, a circular polyribonucleotide may encode an IRES operably linked to an open reading frame encoding a first polypeptide, a 2A, and a second polypeptide.In some embodiments, the plurality of polypeptides may be separated by a protease cleavage site (e.g., a furin cleavage site). For example, a circular polyribonucleotide may encode an IRES operably linked to an open reading frame encoding a first polypeptide, a protease cleavage site (e.g., a furin cleavage site), and a second polypeptide.In some embodiments, the plurality of polypeptides may be separated by a 2A self-cleaving peptide and a protease cleavage site (e.g., a furin cleavage site). For example, a circular polyribonucleotide may encode an IRES operably linked to an open reading frame encoding a first polypeptide, a 2A, a protease cleavage site (e.g., a furin cleavage site), and a second polypeptide. A circular polyribonucleotide may also encode an IRES operably linked to an open reading frame encoding a first polypeptide, a protease cleavage site (e.g., a furin cleavage site), a 2A, and a second polypeptide. A tandem 2A and furin cleavage site may be referred to as a furin-2A (which includes furin-2A or 2A-furin, arranged in either orientation).Furthermore, the plurality of polypeptides encoded by the circular ribonucleotide may be separated by both IRES and 2A sequences. For example, an IRES may be between one polypeptide and a second polypeptide while a 2A peptide may be between the second polypeptide and the third polypeptide. The selection of a particular IRES or 2A self-cleaving peptide may be used to control the expression level of a polypeptide under control of the IRES or 2A sequence. For example, depending on the IRES and or 2A peptide selected, expression on the polypeptide may be higher or lower.In some embodiments, a circular polyribonucleotide includes at least one cleavage sequence. In some embodiments, the cleavage sequence is adjacent to an expression sequence. In some embodiments, the cleavage sequence is between two expression sequences. In some embodiments, cleavage sequence is included in an expression sequence. In some embodiments, the circular polyribonucleotide includes from 2 to 10 cleavage sequences. In some embodiments, the circular polyribonucleotide includes from 2 to 5 cleavage sequences. In some embodiments, the multiple cleavage sequences are between multiple expression sequences; for example, a circular polyribonucleotide may include three expression sequences two cleavage sequences such that there is a cleavage sequence in between each expression sequence. In some embodiments, the circular polyribonucleotide includes a cleavage sequence, such as in an immolating circRNA or cleavable circRNA or self-cleaving circRNA. In some embodiments, the circular polyribonucleotide includes two or more cleavage sequences, leading to separation of the circular polyribonucleotide into multiple products, e.g., miRNAs, linear RNAs, smaller circular polyribonucleotide, etc.In some embodiments, a cleavage sequence includes a ribozyme RNA sequence. A ribozyme (from ribonucleic acid enzyme, also called RNA enzyme or catalytic RNA) is an RNA molecule that catalyzes a chemical reaction. Many natural ribozymes catalyze either the hydrolysis of one of their own phosphodiester bonds, or the hydrolysis of bonds in other RNA, but they have also been found to catalyze the aminotransferase activity of the ribosome. Catalytic RNA can be “evolved” by in vitro methods. Similar to riboswitch activity discussed above, ribozymes and their reaction products can regulate gene expression. In some embodiments, a catalytic RNA or ribozyme can be placed within a larger non-coding RNA such that the ribozyme is present at many copies within the cell for the purposesof chemical transformation of a molecule from a bulk volume. In some embodiments, aptamers and ribozymes can both be encoded in the same non-coding RNA.In some embodiments, the cleavage sequence encodes a cleavable polypeptide linker. For example, a polyribonucleotide may encode two or more polypeptides, e.g., where the two or more polypeptides are encoded by a single open-reading frame (ORF). For example, two or more polypeptides may be encoded by a single open-reading frame, the expression of which is controlled by an IRES. In some embodiments, the ORF further encodes a polypeptide linker, e.g., such that the expression product of the ORF encodes two or more polypeptides each separated by a sequence encoding a polypeptide linker (e.g., a linker of 5-200, 5 to 100, 5 to 50, 5 to 20, 50 to 100, or 50 to 200 amino acids). The polypeptide linker may include a cleavage site, for example, a cleavage site recognized and cleaved by a protease (e.g., an endogenous protease in a subject following administration of the polyribonucleotide to that subject). In such embodiments, a single expression product including the amino acid sequence of two or more polypeptides is cleaved upon expression, such that the two or more polypeptides are separated following expression. Exemplary protease cleavage sites are known to those of skill in the art, for example, amino acid sequences that act as protease cleavage sites recognized by a metalloproteinase (e.g., a matrix metalloproteinase (MMP), such as any one or more of MMPs 1 -28), a disintegrin and metalloproteinase (ADAM, such as any one or more of ADAMs 2, 7-12, 15, 17-23, 28-30 and 33), a serine protease (e.g., furin), urokinase-type plasminogen activator, matriptase, a cysteine protease, an aspartic protease, or a cathepsin protease. In some embodiments, the protease is MMP9 or MMP2. In some embodiments, the protease is matriptase.In some embodiments, a circular polyribonucleotide described herein is an immolating circular polyribonucleotide, a cleavable circular polyribonucleotide, or a self-cleaving circular polyribonucleotide. A circular polyribonucleotide can deliver cellular components including, for example, RNA, long non-coding RNA (IncRNA), long intergenic non-coding RNA (lincRNA), microRNA (miRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), small nucleolar RNA (snoRNA), non-coding RNA (ncRNA), small interfering RNA (siRNA), or small hairpin RNA (shRNA). In some embodiments, a circular polyribonucleotide includes miRNA separated by (i) self-cleavable elements; (ii) cleavage recruitment sites; (iii) degradable linkers; (iv) chemical linkers; and / or (v) spacer sequences. In some embodiments, circRNA includes siRNA separated by (i) self-cleavable elements; (ii) cleavage recruitment sites (e.g., ADAR); (iii) degradable linkers (e.g., glycerol); (iv) chemical linkers; and / or (v) spacer sequences. Non-limiting examples of self- cleavable elements include hammerhead, splicing element, hairpin, hepatitis delta virus (HDV), Varkud Satellite (VS), and glmS ribozymes.Translation Initiation SequencesIn some embodiments, the polyribonucleotide described herein (e.g., the polyribonucleotide cargo of the polyribonucleotide) includes at least one translation initiation sequence. In some embodiments, the polyribonucleotide includes a translation initiation sequence operably linked to an expression sequence.In some embodiments, the polyribonucleotide encodes a polypeptide and may include a translation initiation sequence, e.g., a start codon. In some embodiments, the translation initiation sequence includes a Kozak or Shine-Dalgarno sequence. In some embodiments, the polyribonucleotide includes the translation initiation sequence, e.g., Kozak sequence, adjacent to an expression sequence. In some embodiments, the translation initiation sequence is a non-coding start codon. In someembodiments, the translation initiation sequence, e.g., Kozak sequence, is present on one or both sides of each expression sequence, leading to separation of the expression products. In some embodiments, the polyribonucleotide includes at least one translation initiation sequence adjacent to an expression sequence. In some embodiments, the translation initiation sequence provides conformational flexibility to the polyribonucleotide. In some embodiments, the translation initiation sequence is within a substantially single stranded region of the polyribonucleotide. Further examples of translation initiation sequences are described in paragraphs

[0163] -

[0165] of International Patent Publication No. WO2019 / 118919, which is hereby incorporated by reference in its entirety.The polyribonucleotide may include more than 1 start codon such as, but not limited to, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 50, at least 60 or more than 60 start codons. Translation may initiate on the first start codon or may initiate downstream of the first start codon.In some embodiments, the polyribonucleotide may initiate at a codon which is not the first start codon, e.g., AUG. Translation of the polyribonucleotide may initiate at an alternative translation initiation sequence, such as, but not limited to, ACG, AGG, AAG, CTG / CUG, GTG / GUG, ATA / AUA, ATT / AUU, TTG / UUG. In some embodiments, translation begins at an alternative translation initiation sequence under selective conditions, e.g., stress induced conditions. As a non-limiting example, the translation of the polyribonucleotide may begin at alternative translation initiation sequence, such as ACG. As another non-limiting example, the polyribonucleotide translation may begin at alternative translation initiation sequence, CTG / CUG. As another non-limiting example, the polyribonucleotide translation may begin at alternative translation initiation sequence, GTG / GUG. As another non-limiting example, the polyribonucleotide may begin translation at a repeat-associated non-AUG (RAN) sequence, such as an alternative translation initiation sequence that includes short stretches of repetitive RNA e.g., CGG, GGGGCC (SEQ ID NO: 93), CAG, CTG.Termination ElementsIn some embodiments, the polyribonucleotide described herein (e.g., the polyribonucleotide cargo of the polyribonucleotide) includes least one termination element. In some embodiments, the polyribonucleotide includes a termination element operably linked to an expression sequence. In some embodiments, the polynucleotide lacks a termination element.In some embodiments, the polyribonucleotide includes one or more expression sequences, and each expression sequence may or may not have a termination element. In some embodiments, the polyribonucleotide includes one or more expression sequences, and the expression sequences lack a termination element, such that the polyribonucleotide is continuously translated. Exclusion of a termination element may result in rolling circle translation or continuous expression of expression product.In some embodiments, the circular polyribonucleotide includes one or more expression sequences, and each expression sequence may or may not have a termination element. In some embodiments, the circular polyribonucleotide includes one or more expression sequences, and the expression sequences lack a termination element, such that the circular polyribonucleotide is continuously translated. Exclusion of a termination element may result in rolling circle translation or continuous expression of expression product, e.g., peptides or polypeptides, due to lack of ribosomestalling or fall-off. In such an embodiment, rolling circle translation expresses a continuous expression product through each expression sequence. In some other embodiments, a termination element of an expression sequence can be part of a stagger element. In some embodiments, one or more expression sequences in the circular polyribonucleotide includes a termination element. However, rolling circle translation or expression of a succeeding (e.g., second, third, fourth, fifth, etc.) expression sequence in the circular polyribonucleotide is performed. In such instances, the expression product may fall off the ribosome when the ribosome encounters the termination element, e.g., a stop codon, and terminates translation. In some embodiments, translation is terminated while the ribosome, e.g., at least one subunit of the ribosome, remains in contact with the circular polyribonucleotide.In some embodiments, the circular polyribonucleotide includes a termination element at the end of one or more expression sequences. In some embodiments, one or more expression sequences includes two or more termination elements in succession. In such embodiments, translation is terminated and rolling circle translation is terminated. In some embodiments, the ribosome completely disengages with the circular polyribonucleotide. In some such embodiments, production of a succeeding (e.g., second, third, fourth, fifth, etc.) expression sequence in the circular polyribonucleotide may require the ribosome to reengage with the circular polyribonucleotide prior to initiation of translation. Generally, termination elements include an in-frame nucleotide triplet that signals termination of translation, e.g., UAA, UGA, UAG. In some embodiments, one or more termination elements in the circular polyribonucleotide are frame-shifted termination elements, such as but not limited to, off-frame or -1 and + 1 shifted reading frames (e.g., hidden stop) that may terminate translation. Frame-shifted termination elements include nucleotide triples, TAA, TAG, and TGA that appear in the second and third reading frames of an expression sequence. Frame-shifted termination elements may be important in preventing misreads of mRNA, which is often detrimental to the cell. In some embodiments, the termination element is a stop codon.Further examples of termination elements are described in paragraphs

[0169] -

[0170] of International Patent Publication No. WO2019 / 118919, which is hereby incorporated by reference in its entirety.Untranslated RegionsIn some embodiments, a circular polyribonucleotide includes untranslated regions (UTRs). UTRs of a genomic region including a gene may be transcribed but not translated. In some embodiments, a UTR may be included upstream of the translation initiation sequence of an expression sequence described herein. In some embodiments, a UTR may be included downstream of an expression sequence described herein. In some instances, one UTR for first expression sequence is the same as or continuous with or overlapping with another UTR for a second expression sequence. In some embodiments, the intron is a human intron. In some embodiments, the intron is a full-length human intron, e.g., ZKSCAN1.Exemplary untranslated regions are described in paragraphs

[0197] -

[0201] of International Patent Publication No. WO2019 / 118919, which is hereby incorporated by reference in its entirety.In some embodiments, a circular polyribonucleotide includes a polyA tail. Exemplary polyA tails are described in paragraphs

[0202] -

[0205] of International Patent Publication No. WO2019 / 118919, which is hereby incorporated by reference in its entirety. In some embodiments, a circular polyribonucleotide lacks a polyA tail.In some embodiments, a circular polyribonucleotide includes a UTR with one or more stretches of Adenosines and Uridines embedded within. These AU rich signatures may increase turnover rates of the expression product.Introduction, removal, or modification of UTR AU rich elements (AREs) may be useful to modulate the stability, or immunogenicity (e.g., the level of one or more marker of an immune or inflammatory response) of the circular polyribonucleotide. When engineering specific circular polyribonucleotides, one or more copies of an ARE may be introduced to the circular polyribonucleotide and the copies of an ARE may modulate translation and / or production of an expression product. Likewise, AREs may be identified and removed or engineered into the circular polyribonucleotide to modulate the intracellular stability and thus affect translation and production of the resultant protein.It should be understood that any UTR from any gene may be incorporated into the respective flanking regions of the circular polyribonucleotide.In some embodiments, a circular polyribonucleotide lacks a 5’-UTR and is competent for protein expression from its one or more expression sequences. In some embodiments, the circular polyribonucleotide lacks a 3’-UTR and is competent for protein expression from its one or more expression sequences. In some embodiments, the circular polyribonucleotide lacks a polyA tail and is competent for protein expression from its one or more expression sequences. In some embodiments, the circular polyribonucleotide lacks a termination element and is competent for protein expression from its one or more expression sequences. In some embodiments, the circular polyribonucleotide lacks an internal ribosomal entry site and is competent for protein expression from its one or more expression sequences. In some embodiments, the circular polyribonucleotide lacks a cap and is competent for protein expression from its one or more expression sequences. In some embodiments, the circular polyribonucleotide lacks a 5’-UTR, a 3 -UTR, and an IRES, and is competent for protein expression from its one or more expression sequences. In some embodiments, the circular polyribonucleotide includes one or more of the following sequences: a sequence that encodes one or more miRNAs, a sequence that encodes one or more replication proteins, a sequence that encodes an exogenous gene, a sequence that encodes a therapeutic, a regulatory element (e.g., translation modulator, e.g., translation enhancer or suppressor), a translation initiation sequence, one or more regulatory nucleic acids that targets endogenous genes (e.g., siRNA, IncRNAs, shRNA), and a sequence that encodes a therapeutic mRNA or protein.In some embodiments, a circular polyribonucleotide lacks a 5’-UTR. In some embodiments, the circular polyribonucleotide lacks a 3’-UTR. In some embodiments, the circular polyribonucleotide lacks a polyA tail. In some embodiments, the circular polyribonucleotide lacks a termination element. In some embodiments, the circular polyribonucleotide lacks an internal ribosomal entry site. In some embodiments, the circular polyribonucleotide lacks degradation susceptibility by exonucleases. In some embodiments, the fact that the circular polyribonucleotide lacks degradation susceptibility can mean that the circular polyribonucleotide is not degraded by an exonuclease, or only degraded in the presence of an exonuclease to a limited extent, e.g., that is comparable to or similar to in the absence of exonuclease. In some embodiments, the circular polyribonucleotide is not degraded by exonucleases. In some embodiments, the circular polyribonucleotide has reduced degradation when exposed to exonuclease. In some embodiments, the circular polyribonucleotide lacks binding to a cap-binding protein. In some embodiments, the circular polyribonucleotide lacks a 5’ cap.Spacer SequencesIn some embodiments, the polyribonucleotide described herein includes one or more spacer sequences. In some embodiments, the moiety that specifically bind a region of the circular polyribonucleotide binds a region of the circular polyribonucleotide includes one or more spacers. A spacer refers to any contiguous nucleotide sequence (e.g., of one or more nucleotides) that provides distance or flexibility between two adjacent polynucleotide regions. Spacers may be present in between any of the nucleic acid elements described herein. Spacer may also be present within a nucleic acid element described herein.For example, wherein a nucleic acid includes any two or more of the following elements: (A) a 3' catalytic intron fragment; (B) a 3’ splice site; (C) a 3’ exon fragment; (D) a polyribonucleotide cargo; (E) a 5’ exon fragment; (F) a 5’ splice site; and (G) a 5' catalytic intron fragment; a spacer region may be present between any one or more of the elements. Any of elements (A), (B), (C), (D), (E), (F), or (G) may be separated by a spacer sequence, as described herein. For example, there may be a spacer between (A) and (B), between (B) and (C), between (C) and (D), between (D) and (E), between (E) and (F), or between (F) and (G).A spacer sequences may be used to separate an IRES from adjacent structural elements to martini the structure and function of the IRES or the adjacent element. A spacer can be specifically engineered depending on the IRES. In some embodiments, an RNA folding computer software, such as RNAFold, can be utilized to guide designs of the various elements of the vector, including the spacers.The spacer may be, e.g., at least 5 (e.g., at least 10, at least 15, at least 20) ribonucleotides in length. In some embodiments, each spacer region is at least 5 (e.g., at least 10, at least 15, at least 20) ribonucleotides in length. Each spacer region may be, e.g., from 5 to 500 (e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, or 500) ribonucleotides in length. The first spacer region, the second spacer region, or the first spacer region and the second spacer region may include a polyA tail (or, e.g., polyA sequence). The first spacer region, the second spacer region, or the first spacer region and the second spacer region may include a polyA-C tail (or, e.g., polyA-C sequence). In some embodiments, the first spacer region, the second spacer region, or the first spacer region and the second spacer region includes a polyA-G tail (or, e.g., polyA-G sequence). In some embodiments, the first spacer region, the second spacer region, or the first spacer region and the second spacer region includes a polyA-U tail (or, e.g., polyA-U sequence). In some embodiments, the first spacer region, the second spacer region, or the first spacer region and the second spacer region includes a random sequence.In some embodiments, the spacer sequence can be, for example, at least 10 nucleotides in length, at least 15 nucleotides in length, or at least 30 nucleotides in length. In some embodiments, the spacer sequence is at least 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25 or 30 nucleotides in length. In some embodiments, the spacer sequence is no more than 100, 90, 80, 70, 60, 50, 45, 40, 35 or 30 nucleotides in length. In some embodiments the spacer sequence is from 20 to 50 nucleotides in length. In certain embodiments, the spacer sequence is 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49 or 50 nucleotides in length.The spacer sequences can be polyA tails, polyA-C tails, polyC tails, or poly-U tails.In some embodiments, the spacer sequences can be polyA-T, polyA-C, polyA-G, or a random sequence.Exemplary spacer sequences are described in paragraphs

[0293] -

[0302] of International Patent Publication No. WO2019 / 1 18919, which is hereby incorporated by reference in its entirety.ModificationsA polyribonucleotide (e.g., circular polyribonucleotide) as described herein may include one or more substitutions, insertions and / or additions, deletions, and covalent modifications with respect to reference sequences, in particular, the parent polyribonucleotide, are included within the scope of this disclosure.In some embodiments, a circular polyribonucleotide includes one or more post-transcriptional modifications (e.g., capping, cleavage, polyadenylation, splicing, polyA tail, methylation, acylation, phosphorylation, methylation of lysine and arginine residues, acetylation, and nitrosylation of thiol groups and tyrosine residues, etc.). The one or more post-transcriptional modifications can be any post- transcriptional modification, such as any of the more than one hundred different nucleoside modifications that have been identified in RNA (Rozenski, J, Crain, P, and McCloskey, J. (1999). The RNA Modification Database: 1999 update. Nucl Acids Res 27: 196-197). In some embodiments, the first isolated nucleic acid includes messenger RNA (mRNA). In some embodiments, the polyribonucleotide includes at least one nucleoside selected from the group such as those described in

[0311] of International Patent Publication No. WO2019 / 1 18919, which is incorporated herein by reference in its entirety.A polyribonucleotide may include any useful modification, such as to the sugar, the nucleobase, or the internucleoside linkage (e.g., to a linking phosphate / to a phosphodiester linkage / to the phosphodiester backbone). One or more atoms of a pyrimidine nucleobase may be replaced or substituted with optionally substituted amino, optionally substituted thiol, optionally substituted alkyl (e.g., methyl or ethyl), or halo (e.g., chloro or fluoro). In certain embodiments, modifications (e.g., one or more modifications) are present in each of the sugar and the internucleoside linkage. Modifications may be modifications of ribonucleic acids (RNAs) to deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs) or hybrids thereof). Additional modifications are described herein.In some embodiments, a polyribonucleotide includes at least one N(6)methyladenosine (m6A) modification to increase translation efficiency. In some embodiments, the m6A modification can reduce immunogenicity (e.g., reduce the level of one or more marker of an immune or inflammatory response) of the circular polyribonucleotide.In some embodiments, a modification may include a chemical or cellular induced modification. For example, some non-limiting examples of intracellular RNA modifications are described by Lewis and Pan in “RNA modifications and structures cooperate to guide RNA-protein interactions” from Nat Reviews Mol Cell Biol, 2017, 18:202-210.In some embodiments, chemical modifications to the ribonucleotides of a circular polyribonucleotide may enhance immune evasion. The circular polyribonucleotide may be synthesized and / or modified by methods well established in the art, such as those described in "Current protocols in nucleic acid chemistry," Beaucage, S.L. et al. (Eds.), John Wiley & Sons, Inc., New York, NY, USA, which is hereby incorporated herein by reference. Modifications include, for example, end modifications, e.g., 5'end modifications (phosphorylation (mono-, di- and tri-), conjugation, inverted linkages, etc.), 3' end modifications (conjugation, DNA nucleotides, inverted linkages, etc.), base modifications (e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners), removal of bases (abasic nucleotides), or conjugated bases. The modified ribonucleotide bases may also include 5-methylcytidine and pseudouridine. In some embodiments, base modifications may modulate expression, immune response, stability, subcellular localization, to name a few functional effects, of the circular polyribonucleotide. In some embodiments, the modification includes a bi-orthogonal nucleotide, e.g., an unnatural base. See for example, Kimoto et al, Chem Commun (Camb), 2017, 53:12309, DOI: 10.1039 / c7cc06661a, which is hereby incorporated by reference.In some embodiments, sugar modifications (e.g., at the 2' position or 4' position) or replacement of the sugar one or more ribonucleotides of the circular polyribonucleotide may, as well as backbone modifications, include modification or replacement of the phosphodiester linkages. Specific examples of circular polyribonucleotide include, but are not limited to, circular polyribonucleotide including modified backbones or no natural internucleoside linkages such as internucleoside modifications, including modification or replacement of the phosphodiester linkages. Circular polyribonucleotides having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. For the purposes of this application, and as sometimes referenced in the art, modified RNAs that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. In particular embodiments, the circular polyribonucleotide will include ribonucleotides with a phosphorus atom in its internucleoside backbone.Modified polyribonucleotide backbones may include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates such as 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates such as 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed salts and free acid forms are also included. In some embodiments, the circular polyribonucleotide may be negatively or positively charged.The modified nucleotides, which may be incorporated into the polyribonucleotide, can be modified 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 modified by replacing one or more of the oxygen atoms with a different substituent. Further, the modified nucleosides and nucleotides can include the wholesale replacement of an unmodified phosphate moiety with another internucleoside linkage as described herein. Examples of modified 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 modified by the replacement of a linking oxygen with nitrogen (bridged phosphoramidates), sulfur (bridged phosphorothioates), and carbon (bridged methylenephosphonates).The a-thio substituted phosphate moiety is provided to confer stability to RNA and DNA polymers through the unnatural phosphorothioate backbone linkages. Phosphorothioate DNA and RNA have increased nuclease resistance and subsequently a longer half-life in a cellular environment. Phosphorothioate linked to the circular polyribonucleotide is expected to reduce the innate immune response through weaker binding / activation of cellular innate immune molecules.In specific embodiments, a modified nucleoside includes an alpha-thio-nucleoside (e.g., 5'-0-(1 - thiophosphate)-adenosine, 5'-0-(1-thiophosphate)-cytidine (a-thio-cytidine), 5'-0-(1-thiophosphate)- guanosine, 5'-0-(1-thiophosphate)-uridine, or 5'-0-(1-thiophosphate)-pseudouridine).Other internucleoside linkages that may be employed according to the present disclosure, including internucleoside linkages which do not contain a phosphorous atom, are described herein.In some embodiments, a circular polyribonucleotide may include one or more cytotoxic nucleosides. For example, cytotoxic nucleosides may be incorporated into circular polyribonucleotide, such as bifunctional modification. Cytotoxic nucleoside may include, but are not limited to, adenosine arabinoside, 5-azacytidine, 4'-thio-aracytidine, cyclopentenylcytosine, cladribine, clofarabine, cytarabine, cytosine arabinoside, 1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-cytosine, decitabine, 5- fluorouracil, fludarabine, floxuridine, gemcitabine, a combination of tegafur and uracil, tegafur ((RS)-5- fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1 H,3H)-dione), troxacitabine, tezacitabine, 2'-deoxy-2'- methylidenecytidine (DMDC), and 6-mercaptopurine. Additional examples include fludarabine phosphate, N4-behenoyl-1 -beta-D- arabinofuranosylcytosine, N4-octadecyl-1 -beta-D-arabinofuranosylcytosine, N4- palmitoyl-1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine, and P-4055 (cytarabine 5'- elaidic acid ester).A polyribonucleotide may or may not be uniformly modified along the entire length of the molecule. For example, one or more or all types of nucleotides (e.g., naturally occurring nucleotides, purine or pyrimidine, or any one or more or all of A, G, U, C, I, pU) may or may not be uniformly modified in the circular polyribonucleotide, or in a given predetermined sequence region thereof. In some embodiments, the circular polyribonucleotide includes a pseudouridine. In some embodiments, the circular polyribonucleotide includes an inosine, which may aid in the immune system characterizing the circular polyribonucleotide as endogenous versus viral RNAs. The incorporation of inosine may also mediate improved RNA stability / reduced degradation. See for example, Yu, Z. et al. (2015) RNA editing by ADAR1 marks dsRNA as “self. Cell Res. 25, 1283-1284, which is incorporated by reference in its entirety.In some embodiments, all nucleotides in a polyribonucleotide (or in a given sequence region thereof) are modified. In some embodiments, the modification may include an m6A, which may augment expression; an inosine, which may attenuate an immune response; pseudouridine, which may increase RNA stability, or translational readthrough (stagger element), an m5C, which may increase stability; and a 2,2,7-trimethylguanosine, which aids subcellular translocation (e.g., nuclear localization).Different sugar modifications, nucleotide modifications, and / or internucleoside linkages (e.g., backbone structures) may exist at various positions in a circular polyribonucleotide. One of ordinary skill in the art will appreciate that the nucleotide analogs or other modification(s) may be located at any position(s) of the circular polyribonucleotide, such that the function of the circular polyribonucleotide is not substantially decreased. A modification may also be a non-coding region modification. The circular polyribonucleotide may include from about 1% to about 100% modified nucleotides (either in relation tooverall nucleotide content, or in relation to one or more types of nucleotide, i.e. any one or more of A, G, U or C) or any intervening percentage (e.g., from 1% to 20%>, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 20% to 95%, from 20% to 100%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 50% to 95%, from 50% to 100%, from 70% to 80%, from 70% to 90%, from 70% to 95%, from 70% to 100%, from 80% to 90%, from 80% to 95%, from 80% to 100%, from 90% to 95%, from 90% to 100%, and from 95% to 100%).Production of circular polyribonucleotidesThe disclosure provides methods for producing circular polyribonucleotides complexed with a targeting moiety, including, e.g., recombinant technology or chemical synthesis. For example, a DNA molecule used to produce an RNA circle can include a DNA sequence of a naturally occurring original nucleic acid sequence, a modified version thereof, or a DNA sequence encoding a synthetic polypeptide not normally found in nature (e.g., chimeric molecules or fusion proteins). DNA and RNA molecules can be modified using a variety of techniques including, but not limited to, classic mutagenesis techniques and recombinant techniques, such as site- directed mutagenesis, chemical treatment of a nucleic acid molecule to induce mutations, restriction enzyme cleavage of a nucleic acid fragment, ligation of nucleic acid fragments, polymerase chain reaction (PCR) amplification or mutagenesis of selected regions of a nucleic acid sequence, synthesis of oligonucleotide mixtures and ligation of mixture groups to "build" a mixture of nucleic acid molecules and combinations thereof.The circular polyribonucleotides may be prepared according to any available technique, including, but not limited to chemical synthesis and enzymatic synthesis. In some embodiments, a linear primary construct or linear RNA may be cyclized or concatenated to create a circRNA described herein. The mechanism of cyclization or concatenation may occur through methods such as, e.g., chemical, enzymatic, splint ligation, or ribozyme-catalyzed methods. The newly formed 5’-3’ linkage may be an intramolecular linkage or an intermolecular linkage. For example, a splint ligase, such as a SplintR® ligase, can be used for splint ligation. According to this method, a single stranded polynucleotide (splint), such as a single-stranded DNA or RNA, can be designed to hybridize with both termini of a linear polyribonucleotide, so that the two termini can be juxtaposed upon hybridization with the single-stranded splint. Splint ligase can thus catalyze the ligation of the juxtaposed two termini of the linear polyribonucleotide, generating a circRNA. In some embodiments, a DNA or RNA ligase may be used in the synthesis of the circular polynucleotides. As a non-limiting example, the ligase may be a circ ligase or circular ligase.In another example, either the 5' or 3' end of the linear polyribonucleotide can encode a ligase ribozyme sequence such that during in vitro transcription, the resultant linear circRNA includes an active ribozyme sequence capable of ligating the 5' end of the linear polyribonucleotide to the 3' end of the linear polyribonucleotide. The ligase ribozyme may be derived from the Group I Intron, Hepatitis Delta Virus, Hairpin ribozyme or may be selected by SELEX (systematic evolution of ligands by exponential enrichment).In another example, a linear polyribonucleotide may be cyclized or concatenated by using at least one non-nucleic acid moiety. For example, the at least one non-nucleic acid moiety may react with regions or features near the 5' terminus or near the 3' terminus of the linear polyribonucleotide in order to cyclize or concatenate the linear polyribonucleotide. In another example, the at least one non-nucleic acid moiety may be located in or linked to or near the 5' terminus or the 3' terminus of the linear polyribonucleotide. The non-nucleic acid moieties may be homologous or heterologous. As a non-limiting example, the non-nucleic acid moiety may be a linkage such as a hydrophobic linkage, ionic linkage, a biodegradable linkage or a cleavable linkage. As another non-limiting example, the non-nucleic acid moiety is a ligation moiety. As yet another non-limiting example, the non-nucleic acid moiety may be an oligonucleotide or a peptide moiety, such as an aptamer or a non-nucleic acid linker as described herein.In another example, linear polyribonucleotides may be cyclized or concatenated by self-splicing. In some embodiments, the linear polyribonucleotides may include loop E sequence to self-ligate. In another embodiment, the linear polyribonucleotides may include a self-circularizing intron, e.g., a 5' and 3’ slice junction, or a self-circularizing catalytic intron such as a Group I, Group II or Group III Introns. Nonlimiting examples of group I intron self- splicing sequences may include self-splicing permuted intron- exon sequences derived from T4 bacteriophage gene td, and the intervening sequence (IVS) rRNA of Tetrahymena.In another example, a linear polyribonucleotide may be cyclized or concatenated by a non-nucleic acid moiety that causes an attraction between atoms, molecular surfaces at, near, or linked to the 5' and 3' ends of the linear polyribonucleotide. The one or more linear polyribonucleotides may be cyclized or concatenated by intermolecular forces or intramolecular forces. Non-limiting examples of intermolecular forces include dipole-dipole forces, dipole-induced dipole forces, induced dipole-induced dipole forces, Van der Waals forces, and London dispersion forces. Non-limiting examples of intramolecular forces include covalent bonds, metallic bonds, ionic bonds, resonant bonds, agnostic bonds, dipolar bonds, conjugation, hyperconjugation and antibonding.In another example, the linear polyribonucleotide may include a ribozyme RNA sequence near the 5' terminus and near the 3' terminus. The ribozyme RNA sequence may covalently link to a peptide when the sequence is exposed to the remainder of the ribozyme. The peptides covalently linked to the ribozyme RNA sequence near the 5’ terminus and the 3 ‘terminus may associate with each other, thereby causing a linear polyribonucleotide to cyclize or concatenate. In another example, the peptides covalently linked to the ribozyme RNA near the 5' terminus and the 3' terminus may cause the linear primary construct or linear mRNA to cyclize or concatenate after being subjected to ligated using various methods known in the art such as, but not limited to, protein ligation. Non-limiting examples of ribozymes for use in the linear primary constructs or linear polyribonucleotides of the present invention or a non-exhaustive listing of methods to incorporate or covalently link peptides are described in US patent application No. US20030082768, the contents of which is here in incorporated by reference in its entirety.In yet another example, chemical methods of circularization may be used to generate the circular polyribonucleotide. Such methods may include, but are not limited to click chemistry (e.g., alkyne and azide-based methods, or clickable ba...

Claims

CLAIMS 1. A complex comprising A and Xn(L-B)z, wherein A is a circular polyribonucleotide, each X is independently a moiety that binds specifically to a region of A, each L is independently a linker, each B is independently a targeting moiety, wherein n is an integer from 1 to 20, and wherein z is an integer from 1 to 5.

2. The complex of claim 1, wherein n is an integer from 2 to 20.

3. The complex of claim 1, wherein n is an integer from 1 to 5.

4. The complex of any one of claims 1-3, wherein z is an integer from 1 to 3.

5. The complex of claim 4, wherein z is 1.

6. The complex of claim 4, wherein z is 2.

7. The complex of any one of claims 1-6, wherein Xn(L-B)z comprises Xn(L-B1)z and Xn(L-B2)z, where B1 is a first targeting moiety and B2 is a second targeting moiety.

8. The complex of any one of claims 1-7, wherein Xn(L-B)z comprises Xn(L1-B)z and Xn(L2-B)z, where L1 is a first linker and L2 is a second linker.

9. The complex of any one of claims 1-8, wherein Xn(L-B)z comprises X1-(L-B)z and X2-(L-B)z, where X1 is a first moiety that binds specifically to a first region of A and X2 is a second moiety that binds specifically to a second region of A.

10. The complex of any one of claims 1-9, wherein Xn(L-B)z comprises B1-L- X-L-B2, where B1 is a first targeting moiety and B2 is a second targeting moiety.

11. The complex of any one of claims 1-10, wherein Xn(L-B)z comprises B-L1-X-L2-B, where L1 is a first linker and L2 is a second linker.

12. The complex of any one of claims 1-11, wherein the targeting moiety comprises: (a) a small molecule, optionally, folic acid, urea, α-mannose, high mannose, ursodeoxycholic acid, an endosomal escape agent, or lithocholic acid; or (b) a polypeptide, optionally, a cell-penetrating peptide, ASSLNIA, M12, RGD, melittin, LPS- binding protein (LBP) peptide, an adipose-homing peptide, an endolytic peptide, an antibody or a target- binding fragment thereof, a nanobody; or (c) a carbohydrate, optionally, a saccharide, a disaccharide, a polysaccharide, mannose, galactose, glucose, mannose 6-phosphate, or GalNAc, optionally, a mono-GalNAc, a di-GalNAc, a tri- GalNAc, or a tetra-GalNAc; or(d) a lipid, optionally, a fatty acid, optionally, a saturated, monounsaturated, or polyunsaturated fatty acid, or a branched or unbranched chain comprising from 4 to 40 main-chain carbon atoms, a steroid or sterol, optionally, cholesterol, tocopherol, ursodeoxycholic acid, or lithocholic acid, a fat-soluble vitamin, optionally, vitamin A, vitamin D, vitamin E, vitamin K, or an analog or metabolite thereof, a phospholipid, optionally, phosphatidylcholine, phosphocholine (PC), PC-docosahexaenoic acid (PC- DHA), PC-docosanoic acid (PC-DCA), PC-eicosapentaenoic acid (PC-EPA), PC-lithocholic acid (PC-LA), PC-retinoic acid (PC-RA), or PC-α-tocopherol succinate (PC-TS); or (e) a nucleic acid, optionally, an oligonucleotide or an aptamer; or (f) a combination thereof.

13. The complex of claim 12, wherein the fatty acid comprises squalene, stearic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, lauric acid, docosahexanoic acid (DHA), docosanoic acid (DCA), eicosapentaenoic acid (EPA), octadecanoic acid, myristic acid, anadamide, α-tocopherol, α-tocopherol succinate, or a retinoic acid.

14. The complex of any one of claims 1-13, wherein the linker: (i) is a bond; or (ii) comprises 1 to 250 backbone atoms, wherein the backbone atoms are selected from C, N, O, and S; or (iii) comprises an oligonucleotide; or (iv) comprises a polypeptide; or (v) comprises at least one PEG unit, optionally, PEG2-PEG10,000; or (vi) comprises at least one TEG unit, optionally, TEG2-TEG10,000; or (vii) is an enzymatically cleavable linker.

15. The complex of claim 14, wherein the linker has a length of at least 0.1 nm, optionally wherein the linker has a length of from 0.1 nm to 20 nm.

16. The complex of claim 14 or 15, wherein the linker is further conjugated to avidin.

17. The complex of claim 16, wherein the avidin binds from 1 to 4 targeting moieties, optionally wherein the targeting moieties are conjugated to at least one biotin compound.

18. The complex of any one of claims 1-17, wherein X is an oligonucleotide, optionally wherein the oligonucleotide comprises a ribonucleic acid, a deoxyribonucleic acid, a peptide nucleic acid, a locked nucleic acid, or a glycol nucleic acid.

19. The complex of claim 18, wherein the circular polyribonucleotide is bound to from 1 to 100, 1 to 50, 1 to 20, or 1 to 10 oligonucleotides, wherein each oligonucleotide is complexed to at least one targeting moiety.

20. The complex of claim 19, wherein the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 2 to 10, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 oligonucleotides wherein each oligonucleotide is complexed to at least one targeting moiety.

21. The complex of claim 18, wherein the oligonucleotide is from 5 to 100 nucleotides in length.

22. The complex of any one of claims 18-21, wherein the circular polynucleotide comprises one or more binding regions each comprising from 5 to 200 ribonucleotides, wherein each binding region binds to an oligonucleotide.

23. The complex of any one of claims 18-22, wherein each binding region comprises at least 50%, 60%, 70%, 80%, 90%, or 100% complementarity to the oligonucleotide.

24. The complex of any one of claims 1-17, wherein X is a polypeptide.

25. The complex of claim 24, wherein the polypeptide comprises an RNA recognition motif wherein the RNA recognition motif is selected from a K homology domain, zinc finger motif, Pumilio homology domain, pentatricopeptide repeat domain, pseudouridine synthase and archaeosine transglycosylase domain, THUMP domain, YT521-B homology domain, double stranded RNA binding domain, helicase domain, cold shock domain, S1 domain, Sm domain, La motif, Piwi-Argonaute-Zwille domain, or intrinsically disordered region.

26. The complex of claim 24 or 25, wherein the circular polyribonucleotide is bound to from 1 to 100, 1 to 50, 1 to 20, or 1 to 10 polypeptides, wherein each polypeptide is complexed to at least one targeting moiety.

27. The complex of claim 24 or 25, wherein the circular polyribonucleotide is bound to from 2 to 100, 2 to 50, 2 to 20, 2 to 10, 5 to 100, 5 to 50, 5 to 20, 5 to 10, 10 to 100, 10 to 50, or 10 to 20 polypeptides wherein each polypeptide is complexed to at least one targeting moiety.

28. The complex of any one of claims 25-27, wherein the circular polyribonucleotide comprises one or more protein binding regions each comprising from 5 to 200 ribonucleotides, wherein each protein binding region binds to a polypeptide.

29. The complex of any one of claims 1-28, wherein the circular polyribonucleotide further comprises at least one coding region.

30. The complex of claim 29, wherein the at least one coding region comprises an internal ribosomal entry site (IRES) operably linked to an expression sequence encoding a polypeptide.

31. The complex of any one of claims 1-30, wherein the circular polyribonucleotide comprises one or more binding regions each comprising from 5 to 200 ribonucleotides, wherein each binding region binds to X.

32. The complex of claim 31, wherein the binding region is contained within or overlaps in-part with an expression sequence or with a spacer region.

33. The complex of claim 31 or 32, wherein the binding region is not contained within nor does it overlap in-part with an IRES.

34. The complex of any one of claims 31-33 wherein: (i) the 3’ end of the binding region is at least 5 ribonucleotides from 5’ end of the IRES; (ii) the 3’ end of the binding region is from 5 to 200 ribonucleotides from 5’ end of the IRES; (iii) the 5’ end of the binding region is at least 5 ribonucleotides from 3’ end of the IRES; or (iv) the 5’ end of the binding region is from 5 to 200 ribonucleotides from 3’ end of the IRES.

35. The complex of any one of claims 1-30, wherein the circular polyribonucleotide comprises the following elements, arranged in the following order: (i) a first spacer region; (ii) at least one coding region comprising an internal ribosomal entry site (IRES) operably linked to an expression sequence encoding a polypeptide; (iii) optionally a second spacer region; and (iv) a binding region comprising from 5 to 200 ribonucleotides, wherein the binding region binds to X.

36. The complex of any one of claims 1-34, wherein the circular polyribonucleotide comprises the following elements, arranged in the following order: (i) a first spacer region; (ii) a target binding region comprising at least one aptamer or at least ribozyme sequence; (iii) optionally a second spacer region; and (iv) a binding region comprising from 5 to 200 ribonucleotides, wherein the binding region binds to X.

37. The complex of claim 35 or 36, wherein the first spacer region comprises 10 to 500 ribonucleotides.

38. The complex of any one of claims 35-37, wherein the second spacer region comprises 10-500 ribonucleotides.

39. The complex of claim 35, wherein the binding region is contained within or overlaps in-part with the expression sequence.

40. The complex of any one of claims 35-39, wherein (i) the binding region is contained within or overlaps the first spacer region; or (ii) the binding region is contained within or overlaps the second spacer region.

41. The complex of any one of claims 35-40, wherein the first spacer and second spacer are adjacent to one another.

42. The complex of claim 41, wherein the binding region overlaps the first and second spacer regions.

43. The complex of claim 35, wherein the binding region is not contained within nor does it overlap in-part with the expression sequence or with the first or second spacer region.

44. The complex of any one of claims 1-43, wherein (i) the circular polyribonucleotide comprises at least 1,000 ribonucleotides; or (ii) the circular polyribonucleotide comprises from 1,000 to 20,000 ribonucleotides 45. The complex of claim 42, wherein the circular polyribonucleotide comprises at least 3,000 ribonucleotides.

46. The complex of any one of claims 1-45, wherein the circular polyribonucleotide encodes a polypeptide.

47. The complex of any one of claims 1-46, wherein each X comprises a photoreactive crosslinking agent.