REVIEW ARTICLE

A Review of DNA Cryptography

Ling Chu1†, Yanqing Su1†, Xiangyu Yao1, Peng Xu1,2,3*, and Wenbin Liu1,3*
Citation: Chu L, Su Y, Yao X, Xu P,
1
Institute of Computing Science and Technology, Guangzhou University, Guangzhou, Guangdong, China. Liu W. A Review of DNA Cryptography.
2 Intell. Comput. 2025;4:Article
School of Computer Science of Information Technology, Qiannan Normal University for Nationalities,
0106. https://doi.org/10.34133/
Duyun, Guizhou, China. 3Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image icomputing.0106
Analysis and Application, Guangzhou, Guangdong, China.
Submitted 15 April 2024
Revised 8 July 2024
*Address correspondence to: [email protected] (W.L.); [email protected] (P.X.) Accepted 9 October 2024
†These authors contributed equally to this work. Published 17 January 2025

Copyright © 2025 Ling Chu et al.

Deoxyribonucleic acid (DNA), the oldest natural storage medium, offers a highly promising mode for Exclusive licensee Zhejiang Lab. No
information computing and storage with its high information density, low maintenance costs, and the ability claim to original U.S. Government
to do parallel processing. DNA cryptography is an emerging discipline focused on achieving information Works. Distributed under a Creative
security within this new paradigm. In this paper, we first present the foundational concepts of cryptography Commons Attribution License
and biological technologies involved in DNA cryptography. We then comprehensively review 2 types of DNA (CC BY 4.0).

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cryptography: pseudo-DNA cryptography and natural DNA cryptography. After summarizing and discussing
the security foundations of these cryptographic methods, we highlight the main challenges relating to
measurability, standard protocols, robustness, and operability. Finally, we outline future directions for DNA
cryptography, hoping to facilitate the evolution of this nascent field.

Introduction synthesis, preservation, amplification, sequencing, and decoding)

as shown in Fig. 1. For example, not knowing the key primers
With the rapid development of emerging technologies such as makes it difficult to amplify the target DNA sequences; the trans-
cloud computing and artificial intelligence, global digital data formation of the origami structure makes it difficult to assemble
are growing exponentially and are predicted to exceed 175 ZB the information planted on it; a single-nucleotide mutation could
by 2025 [1]. Mainstream magnetic, optical, and electronic stor- be used to encode information; and the alternative splicing of
age technologies hardly keep pace with the increasing demand gene structure produces wide variability.
for data storage. In addition, they also suffer from limitations in In this paper, we start from the perspective of biological dif-
terms of power consumption, volume, reliability, effective stor- ficulties, reviewing 2 types of DNA cryptography: pseudo-DNA
age duration, etc. Exploring new computational theories and cryptography and natural DNA cryptography [14]. The former
storage media is thus a crucial issue for the sustainable develop- is a biomimetic technology that leverages the complexity of bio-
ment of information technology [2–4]. As early as 1959, Nobel logical difficulties to enhance the performance of binary cryp-
laureate Feynman proposed the concept of molecular-scale tographic systems. The latter directly utilizes DNA molecules to
computing. Subsequently, Wiener and Neiman introduced the construct cryptographic systems and incorporates mathematical
idea of molecular genetic storage [5–7]. In 1994, Turing Award difficulties. We summarize and discuss 3 current challenges: lack
winner Adleman first solved a 7-vertex Hamiltonian path prob- of measurability and standard protocols, operational complexity,
lem with biological enzymes and biochemical techniques [8]. and data integrity. Finally, we envision future directions for DNA
In the following year, Baum proposed the construction of a high- cryptography with the hope of developing a secure DNA storage
capacity database storage system based on deoxyribonucleic acid architecture for large-scale applications.
(DNA) [9]. Adelman and Baum thus opened up the era of bio-
logical computing and DNA storage. Concept of Cryptography
As a promising storage medium, DNA has advantages such as
high density, long lifespan, low maintenance cost, and exceptional Cryptography is the practice and study of techniques that ensure
parallelism [10–12]. In 2023, a French company, Biomemory, data confidentiality, integrity, and authenticity against unauthor-
released the first commercial DNA data storage card, which has ized access and tampering [15]. With the rapid development of
a capacity of 1 KB. As DNA storage approaches practical applica- technologies, cryptography has evolved from a simple substitu-
tion, it is critical to develop biologically compatible security tech- tion to a complex and efficient public-key system. Throughout
nologies to achieve data confidentiality, integrity, and availability the evolution of cryptography, encryption and hiding remain 2
(CIA) in this new storage paradigm. Conventional digital security fundamental security strategies [16].
is based on mathematical difficulties, such as NP-hard problems Encryption secures the confidentiality of information by
[13]. Similarly, DNA cryptography takes advantage of the biologi- converting original information (plaintext) into an incompre-
cal difficulties involved in DNA storage processes (encoding, hensible ciphertext through the use of algorithms and secret

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Fig. 1. DNA cryptography adds a security layer for the data stored in DNA molecules. It takes advantage of the biological difficulties inherent in the various mechanisms and

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technologies of biological information processing, such as encoding, synthesis, amplification, sequencing, and complex structures.

keys [17]. Only the one possessing the correct key can retrieve DNA cryptography experiment to hide the military secret mes-
the original information. There are 2 main types of encryption sage “June 6 Invasion: Normandy” within DNA microdots. As
algorithms: (a) Symmetric encryption algorithms, such as the DNA cryptography is a nascent discipline, advancements are
advanced encryption standard (AES), data encryption standard largely inspired by the principles of conventional cryptography
(DES), and triple DES (3DES) algorithms, use the same key for and have led to methods such as DNA encryption and DNA hid-
both the encryption and decryption processes, typically offering ing, which will be discussed in detail.
fast operation suitable for large-scale information encryption.
(b) Asymmetric encryption algorithms, such as the Rivest– Molecular Biology Background of
Shamir–Adleman (RSA) and elliptic curve cryptography (ECC)
algorithms, also known as public-key encryption, employ a pair DNA Cryptography
of keys: a public key that can be shared openly for encryption To achieve the security of confidential information, DNA cryp-
and a private key that must be kept secret for decryption. This tography utilizes underlying principles and technologies involved
type of encryption algorithm is also commonly used for digital in genetic information processing, such as the triple codons
signatures, secure key exchange, and authentication. for amino acids, alternative splicing, polymerase chain reaction
Hiding conceals secret information by embedding it within (PCR) amplification, and gene manipulation operations [28,29].
nonsensitive data (cover), making it inaccessible or impercep- In this section, we provide a basic introduction to some relevant
tible to unauthorized users [18]. There are 2 main types of hid- biology concepts and biotechnologies.
ing techniques: (a) Steganography conceals secret information
within other media (such as images, audio, video, or docu-
ments), making the existence of the information undetectable. Double helical structure of DNA
This technique is typically applied in scenarios requiring high DNA is composed of 4 deoxyribonucleotide triphosphates
levels of secrecy, such as secret communication or hiding sensi- (dNTPs) [30]. Each dNTP consists of a deoxyribose sugar, a
tive information. (b) Digital watermarking embeds identifying phosphate group, and one nitrogenous base, adenine (A), gua-
information (such as copyright information) into digital media nine (G), cytosine (C), or thymine (T). Phosphodiester bonds
(such as audio, video, or images) to achieve copyright protection link the phosphate group at the 5′ position of one nucleotide
and content authentication. Steganography focuses on imper- to the 3′ position of the next, while the bases adhere to a spe-
ceptible concealment, while digital watermarking demands cific complement rule (A always pairs with T, and G with C).
greater robustness. Following this principle, 2 complementary DNA strands form
DNA cryptography is an extension of conventional cryptog- a stable double helix structure through hydrogen bonds (as
raphy into the field of life sciences, offering new mechanisms for shown in Fig. 2).
information security by exploring the potential capabilities
of biological properties and techniques. Since Adleman dem- Central dogma
onstrated the massive parallelism of DNA computation [8], The central dogma elucidates the basic principles of genetic
researchers have turned their attention to using DNA to decipher information transmission from DNA to ribonucleic acid (RNA)
conventional cryptographic algorithms such as DES [19,20], RSA and ultimately to protein (as shown in Fig. 3). Initially, the
[21,22], NTRU [23], Diffie–Hellman key exchange [24,25], and double helix structure of DNA partially unwinds at specific
knapsack [26]. Concurrently, Clelland et al. [27] conducted a locations. Under the guidance of transcription factors, RNA

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polymerase binds to these locations and moves along the DNA nonessential introns from pre-mRNA, alternative splicing
template to transcribe precursor messenger RNA (pre-mRNA). enriches biological diversity and plays a vital role in the regula-
This pre-mRNA is then processed into mature messenger RNA tion of gene expression, enhancing the complexity of cellular
(mRNA) through splicing and capping. Finally, the ribosome functions.
translates the bonded mRNA into protein. In this process,
64 triplet codons are reduced to 20 standard amino acids, one Enzymatic tools for DNA modification
start signal, and 3 stop signals. Such redundancy is beneficial In genetic engineering, enzymes are crucial in cutting and past-
in minimizing genetic transmission errors [31]. ing single-/double-strand DNA (ssDNA/dsDNA). Restriction
endonucleases recognize and cleave dsDNA at specific nucleo-
Alternative splicing tide sequences. DNA ligases join the ends of 2 DNA strands.
Alternative splicing enables one gene to generate multiple pro- Exonucleases selectively degrade single/double DNA strands
tein variants [32]. By selectively assembling exons and removing by trimming DNA ends or removing excess sequences.
Clustered regularly interspaced short palindromic repeats
(CRISPR) is an advanced gene editing technology that can
precisely locate, cut, and modify specific DNA sequences with
CRISPR-associated (Cas) enzymes [33]. Unlike traditional
enzymatic techniques that recognize particular DNA sequences,
the CRISPR system can edit almost any site by designing spe-
cific guide RNA (gRNA). Moreover, CRISPR-Cas12a possesses
dual cutting capabilities that not only specifically recognize and
precisely edit targeted dsDNA but also indiscriminately cut
ssDNA within the system [34] (Fig. 4).

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DNA hybridization
DNA hybridization is a fundamental technique used in various
applications, including DNA chips, Southern blotting, northern
blotting, in situ hybridization, and PCR primer design. In the
PCR process, the primers first bind to the complementary
sequences, flanking the target region, and then extending along
the target DNA sequence by adding complementary nucleo-
tides. In DNA computing and storage, DNA hybridization is
classified into specific and nonspecific hybridization. The for-
mer means a completely complementary hybridization between
the probe and the target sequences, while the latter represents
a partial hybridization [35].

Base operations
In previous studies, researchers designed base operations as
in digital computing to perform information transformation
Fig. 2. Schematic diagram of the double helical structure of DNA. On the left is shown using 2 DNA sequences [36]. Table 1 shows 3 rules for base
a general schematic of the double helix, while on the right is shown the nucleotide exclusive or (XOR), addition (ADD), and subtraction (SUB)
structure, hydrogen bonds (A–T and C–G pairing), and phosphodiester bonds. operations.

Fig. 3. Schematic diagram of the central dogma. Genetic information is transferred from DNA by transcription to pre-mRNA, spliced to form mRNA, and finally translated
into proteins by ribosomes.

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Fig. 4. Different forms of DNA modification by enzymes. (A) Restriction endonucleases. (B) DNA ligase. (C) Exonucleases. (D) CRISPR-Cas12a.

Table 1. Base exclusive or, addition, and subtraction operation rules

Exclusive or Addition Subtraction

XOR A G C T  + A G C T  - A G C T
A A G C T  A A G C T  A A T C G
G G A T C  G G C T A  G G A T C
C C T A G  C C T A G  C C G A T
T T C G A  T T A G C  T T C G A

Pseudo-DNA Cryptography logistic maps with DNA addition and base complement opera-
tions to scramble image information. This method effectively
“Pseudo-DNA cryptography” refers to introducing biological combines base operations with chaos theory, providing a promis-
complexity into conventional encryption and aims to provide ing perspective for image encryption. In 2012, Liu et al. [39]
enhanced security for binary data. In 2009, Kang Ning devised employed the piecewise linear chaotic map system to scramble a
a text encryption method by simulating the central dogma [37]. DNA-formatted image, simulating the DNA base pairing rules to
Specifically, the plaintext is encoded into DNA sequences, then modify each nucleotide. Zhang et al. [40] encoded and segmented
spliced and translated to produce a protein-formatted cipher- an image into multiple short DNA sequences and utilized
text. The secret key consists of the genetic code table used for the Chen hyperchaotic system for selecting positions to expand,
translation and the patterns and locations of splicing. This truncate, delete, or insert these sequences. Enayatifar et al. [41]
method offers powerful resistance to brute force attacks by encrypted images by integrating genetic algorithms with a logistic
leveraging the complex mechanisms of the gene translation map, effectively reducing the correlation among adjacent pixels.
process. Kalpana and Murali [42] increased encryption complexity by
In 2010, Zhang et al. [38] proposed an image encryption selecting distinct coding rules for different color channels (e.g.,
method (as shown in Fig. 5A) that integrates 1- and 2-dimensional red, green, blue). However, static encoding rules are insufficient

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Fig. 5. Three pseudo-DNA cryptography methods. (A) The image encryption method combines pseudo-DNA operations (highlighted in red) with 1D/2D logistic chaotic maps
[38]. (B) State diagram of the new DNA right-circular and left-circular shift operators, which diffuse secret information at the DNA level by referencing the key base matrices
[44]. (C) The DNA-based Vigenère cipher accomplishes the base-substitution encryption by referencing the key sequence [55].

to defend against complex attacks. In 2019, Chai et al. [43] model with novel asymmetric base operations designed using
employed a chaotic system to dynamically select coding rules matrix calculations. Alawida [50] designed a DNA tree algorithm
for each pixel, designing an image encryption method sensitive and a new chaotic state machine map to encrypt images. The cha-
enough to resist known-plaintext and chosen-plaintext attacks. otic map integrates a finite state machine, while the DNA tree
In 2020, Zefreh [44] introduced 2 cyclic shift algebraic operators randomly generates a table that maps pixel values (0 to 255) to
based on DNA sequences to enhance DNA diffusion as shown in DNA bases (e.g., 150 to TAAA) and guides the performance of
Fig. 5B. Concretely, chaotic systems convert the original image DNA substitution operations (using a substitution box).
and secret key into DNA matrices. Subsequently, the image matri- Besides combining chaotic systems to design pseudo-DNA
ces are diffused at the DNA level by referencing the key matrices image encryption methods, researchers also employ pseudo-
and applying base operations such as addition, subtraction, right- DNA operations to develop other security techniques. Sadeg et al.
circular shift, and left-circular shift. Chidambaram et al. [45] [51] achieved a symmetric block encryption algorithm by design-
combined the chaotic-based key generation system with DNA ing new DNA operation rules and exploiting codon degeneration.
diffusion by base operations, ensuring the CIA of medical images Babu et al. [52] designed a pseudo-DNA communication model
stored in the cloud. To further enhance encryption security, that simulated DNA transcription and cooperative communica-
researchers explored more complex and higher-dimensional cha- tion among organelles. Thangavel and Varalakshmi [53] applied
otic systems. In 2023, Li and Chen [46] proposed a 6-dimensional the central dogma to secure data in the cloud, providing a more
hyperchaotic system and base XOR operations to encrypt color randomized and prudent system in practice. Majumdar et al. [54]
images. In 2024, Yu et al. [47] developed a dynamic encryption utilized the redundancy of alternative splicing to design a substi-
network incorporating 12 types of base operations where a hyper- tution box for encryption and stored related pieces of infor-
chaotic system was used to generate random keys. Wu et al. [48] mation, such as time, date, and owner ID, in introns to ensure
proposed a medical image encryption method consisting of ran- information integrity.
dom DNA encoding and content-aware DNA permutation and Furthermore, researchers utilized the randomness of genetic
diffusion. The former utilizes the piecewise linear chaotic map information to select natural DNA sequences as secret keys. In
system to select different binary-to-base encoding rules for each 2015, Najaftorkaman and Kazazi [55] chose natural DNA from
pixel, while the latter breaks the correlation between adjacent the National Center of Biotechnology Information (NCBI)
pixels using the hyperchaotic Lorenz system and base operations gene library as a secret key to implement the Vigenère cipher
(ADD, SUB, and XOR). Liu et al. [49] proposed a medical image encryption [56] at the DNA level as shown in Fig. 5C. Similarly,
encryption method integrating a new spatiotemporal chaotic Grass et al. [57] used short tandem repeat segments from the

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human genome as keys for secure access to confidential infor- Substituting some specific sites within the cover sequence can
mation, Kolate and Joshi [58] achieved enhanced AES encryp- also hide secret information. Huang et al. [72] converted the cover
tion, and Al-Husainy et al. [59] implemented a lightweight sequence into decimal numbers and then selected hiding sites
internet-of-things encryption system. using the histogram shifting algorithm. In 2019, Sabry et al. [73]
exploited codon degeneracy to conceal information to eliminate
Natural DNA Cryptography unexpected influence on biological functionality. Each amino acid
maps to multiple codons, for instance, amino acid “I” maps to 3
Combined with mathematical difficulties in conventional cryp- codons, where U represents the base uracil: “AUU”, “AUC”, and
tography, natural DNA cryptography explores the potential of “AUA”; replacing “AUU” on the cover DNA sequence with “AUC”
biological difficulties involved in the wet-lab DNA manipulation signifies embedding “001”, while replacing it with “AUA” signifies
process [60]. In this section, we categorize and review advance- embedding “010”. Based on the same characteristic of the codon,
ments in natural DNA cryptography based on different biologi- Alhabeeb et al. [74] further enhanced the hiding capacity using
cal strategies, including DNA encoding, PCR, DNA chips, DNA a 2-tier codon lookup table. Mohammed et al. [75] utilized arti-
origami, and noisy storage channels. ficial neural networks to select hiding sites to achieve high-capac-
ity and safe information hiding. In the same year, Saha et al. [76]
DNA encoding encoded the cover sequence into a balanced tree and replaced all
Encryption can be achieved at the DNA level by designing com- leaf nodes with secret information. Ultimately, they generated the
plex coding rules. In 2004, Gehani et al. [61] proposed a one- embedded cover sequence using a depth-first traversal method
time pad encryption using a codebook of <plain, cipher> DNA to output the balanced tree. This method offers a high capacity
word pairs, as shown in Fig. 6, that can replace plaintext (P) for information hiding, but its security is compromised if the tree
with ciphertext (C). Siddaramappa and Ramesh [62] encrypted structure is leaked. In 2022, Hassan et al. [77] utilized a DNA-
DNA-formatted plaintext by XORing it with selected natural based Huffman coding to encrypt information and designed a
DNA sequences from the NCBI database. Hameed et al. [63] substitution algorithm to conceal the ciphertext within an actual

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independently encoded red, green, and blue image compo- DNA sequence obtained from the NCBI database. Huang et al.
nents into DNA sequences and performed addition operations [78] utilized the adaptive dynamic grouping algorithm to embed
between pairs of these sequences according to specific rules. secret information into quasi-natural pseudo-sequences, which
In 2019, Biswas et al. [64] developed a cryptography based on are generated by a trained long short-term memory model that
the Fibonacci sequence using a dynamic ASCII-to-base conver- learns the statistical properties of natural DNA.
sion table. In 2021, Nandy et al. [65] encoded images using 24
possible quadruplet combinations of ATCG where 16 quadru- Polymerase chain reaction
plets were mapped to the hexadecimal values “0” to “F”, and PCR is a molecular biology technique used to amplify specific
the remaining 8 were assigned to the most frequent pixels to DNA strands in vitro rapidly. PCR plays a crucial role in the
increase storage density and algorithm complexity. In 2022, reading process of DNA storage. By designing specific primers
Satir and Kendirli [66] proposed biotechnical encryption hard- [~20 nucleotides (nt)], even minute quantities of DNA strands
ware incorporating DNA encoding and operations within the can be amplified for sequencing. Without knowing the primer,
Feistel network structure. it is usually difficult to precisely amplify the target sequence.
Information hiding can also be achieved by inserting or sub- Researchers have designed some DNA cryptography methods
stituting specific nucleotides. Insertion hiding typically embeds using PCR primers (as shown in Fig. 7).
secret information at inconspicuous sites in cover DNA sequences. In 2000, Leier et al. [79] proposed a method for DNA cryp-
Menaka [67] combined different base pairing rules with the most tography that mixed secret DNA sequences (with primers) with
significant bit (MSB) algorithm, successfully embedding secret a large volume of irrelevant DNA sequences (without primers).
information into natural DNA. Malathi et al. [68] converted “1 Only with knowledge of the primer sequences can users specifi-
bit of secret information + 3 bits of unrelated information” into cally amplify the secret DNA strands and decrypt the informa-
DNA sequences using quaternary coding. In 2020, Khalifa [69] tion. In 2008, Cui et al. [80] utilized RSA to encrypt information
employed the 8 × 8 Playfair encryption algorithm to encode first, then assembled this ciphertext into a structure consisting
information into short DNA sequences. These sequences were of a forward primer (20 nt) followed by the DNA ciphertext
then randomly concatenated with unrelated sequences, resulting (64 nt) followed by a reverse primer (20 nt). To achieve obfusca-
in a long cover DNA sequence. Na [70] concealed secret informa- tion, these sequences were mixed with numerous DNA strands
tion in single-nucleotide polymorphism regions using genetic that had identical structures but utilized different primers. Zhang
variability. In 2023, Sadia et al. [71] hid secret information within et al. [81] segmented secret information into smaller DNA frag-
a vast cover DNA sequence where the inserted positions were ments, each paired with distinct primers and mixed with decoy
generated by a mathematical function. sequences. The decryption requires precise knowledge of all

Fig. 6. The one-time pad encryption method creates a codebook of <plain, cipher> DNA word pairs to replace plaintext (P) with ciphertext (C) [61].

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Fig. 7. Specific and nonspecific PCR for DNA cryptography. The former specifically amplifies the secret DNA sequences (highlighted in color) with knowledge of the primer,

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while the latter amplifies all DNA sequences, resulting in the secret information being hidden among a sea of irrelevant information.

Fig. 8. The schematic diagram for DNA chip encryption [84]. Two predefined sets of sequences represent “0” and “1”. A randomly selected group of probes is spotted on the
DNA chip. Users can only discriminate between these 2 types of spots using the complementary strands of the probe set of “1”.

primer pairs and the order of these DNA segments. Considering sequences (probes) onto a solid surface and then hybridizing
the security risk of primer leakage, Li et al. [82] designed a them with labeled samples of complementary DNA. The inten-
pre-key mechanism by utilizing the dual cutting capabilities sity of the fluorescence indicates gene expression levels. DNA
of CRISPR/Cas12a. True primers were mixed with decoy prim- chips enable researchers to study gene activity in response to
ers to form a pre-key. Only after the precise cutting of CRISPR/ conditions like diseases or drug treatments, aiding in cancer
Cas12a does this mixture reveal the true key to decrypt the research, drug development, and personalized medicine.
real information. In 2021, Fan et al. [83] utilized Pfu DNA poly- Usually, it is difficult to precisely know the short probes
merase to concatenate 2 DNA molecules of distinct chirality end (~30 nt) spotted on a DNA chip, especially when each spot
to end. This method ensures that natural PCR amplifies only the is mixed with many different probes. In 2007, Lu et al. [84]
misleading information contained in D-DNA. Conversely, the developed a symmetric encryption as shown in Fig. 8. First,
true information encoded in L-DNA can be accessed only they designed 2 sets of DNA probes representing “0” and “1”.
through mirror-image PCR. Then, they printed a randomly selected group of probes from
the corresponding set on each spot of the chip. The biological
DNA chips difficulty comes from the tremendous number of probes for
A DNA chip (or DNA microarray) is a high-throughput tech- “0” or “1” and the versatility of probes in each spot. Only when
nology used to analyze the expression levels of thousands of the probes for “1” are known can the receiver decode the
genes simultaneously. It involves immobilizing short DNA printed ciphertext. When relaxed to nonspecific hybridization,

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each receiver could have his own private keys, which could have Yao et al. [91] proposed an image encryption algorithm based
a high degree of hybridization with the printed spots. Based on on forward error correction DNA codes. In a noisy channel, it
this idea, they designed encryption systems for public keys and is difficult to infer the codes, and their dynamic invocation
digital signatures [85], dynamic broadcast encryption [86], and increases the decryption difficulty at the DNA level. Based on
information hiding [87]. the same idea, Yao et al. [92] introduced DNA hybridization for
pixel replacement and gene mutation for pixel diffusion. Zan
DNA origami et al. [93] proposed an image encryption method based on the
DNA origami is a revolutionary technique in nanotechnology modulation-based storage architecture shown in Fig. 10. The
that enables the precise folding of DNA into complex nano- key idea is to use the unpredictable modulation carrier to encrypt
structures, such as rectangles, squares, tetrahedra, and cubes. images in highly error-prone DNA storage channels. Without
This process begins with computer-aided design, which speci- the true modulation carrier (secret key), numerous base errors
fies sequences for scaffold DNA and staple strands. Upon mix- in DNA sequences cannot be corrected, ensuring that the secret
ing under controlled conditions, the strands self-assemble to information remains undecipherable to attackers. Compared
form intricate shapes. The versatility and precision of DNA with the former 2 methods, this method is feasible for higher-
origami make it a potent tool for creating tailored nanostruc- noise storage channels (≥20%) due to the robustness of modula-
tures with diverse functionalities, such as biosensing and drug tion coding [94]. Chu et al. [95] applied a noisy storage channel
delivery. Moreover, the programmability and addressability of to deniable encryption by using 2 similar modulation carriers
DNA origami provide potential opportunities in information to encode true and fake messages into DNA sequences. The con-
storage, which is usually read by atomic force microscopy. fusion caused by the noisy channel makes it difficult for coercive
In 2013, Wong et al. [88] utilized the competitive binding adversaries to distinguish between the true and fake DNA, allow-
affinities of biotin and desthiobiotin toward streptavidin, employ- ing them to obtain only the “plausible” fake message.
ing biotin as a secret key to selectively reverse the desthiobiotinyl-
ated streptavidin sites on the origami for revealing sensitive

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information. Zhang et al. [89] designed an encryption method Challenges
for braille-encoded information, where a group of specialized Table 2 presents a summary of the main biotechnologies used
staples (serving as keys) could deconstruct the arrangement of in DNA cryptography. The cryptographic complexity of DNA
the biotinylated information positions on the origami (as shown encoding arises from 2 aspects: the dynamic cryptographic pro-
in Fig. 9). Later, Fan et al. [90] developed a DNA origami domino cesses in base coding/operation rules and a sufficiently large key
array based on the same principle to achieve encryption and space (typically ~2n), where n is the encoding length of sequences,
hiding synchronously. usually approximately 200 nt in vitro [96]. For DNA chips and
DNA origami, the relatively high security derives from the large
Noisy storage channels number of possibilities for random combinations of various
One ubiquitous characteristic of DNA storage is insertion– probes (~20 nt) [97] and staples (~30 nt) [98]. The former pro-
deletion–substitution (IDS) errors in the sequenced reads vides possible key combinations when choosing 2,000 probes
because of imperfect synthesis, PCR, and sequencing technolo- to denote “1” and another 2,000 for “0” [84], while the latter
gies. The error rate is 1% to 2% in mainstream next-generation achieves a theoretical key size of over 700 bits (much greater
sequencing and up to 10% for nanopore sequencers [1,10]. In than the 256 bits of AES) when using a 7,249-nt M13mp18 scaf-
the reading process, the sequenced reads are usually clustered fold [89]. The complexity of the noise channel stems from the
in groups that may come from the same encoding sequences. magnitude of the noise level (IDS error rates typically ≤10%)
The decoding process is performed on these clusters using vari- and the encoding length (~200 nt in vitro); the former affects
ous error correction techniques. Researchers have proposed the difficulty of inference, while the latter determines the key
various methods to tackle this problem for reliable information space (typically ~2200). The cryptographic space of PCR is rela-
retrieval [82,85]. From the perspective of information security, tively low because of the limited number of primers. The largest
such a unique noise channel may provide new opportunities orthogonal primer set reported in [99] is approximately 5,625,
for encryption and hiding. and their combinations number less than 8 × 106. Additionally,

Fig. 9. Schematic diagram of DNA origami encryption [89]. Secret information is encoded into a tactile grid pattern and meticulously marked onto the scaffold of DNA origami.
Only with all the correct staples can the scaffold be deconstructed from a disordered state back to a state where the braille information is clearly visible.

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Fig. 10. Schematic diagram of image encryption based on noisy storage channels. On the left is the traditional cryptography process, which implements pixel scrambling
and diffusion; on the right is modulation-based cryptography, which provides further confusion by utilizing noisy storage channels [93]. © 2023 Frontiers. Reprinted, with
permission, from Zan et al. [93].

Table 2. Summary of the biotechnologies used in DNA cryptography

Biotechnology Biological difficulty Security Operability Robustness Information density

DNA encoding Unknown coding/operation rules High Simple Weak High (≥1 bit/nt)
DNA chips Unknown mixed probes High Simple Moderate Low (<<1 bit/nt)
DNA origami Diversity of 3D structures High Complex Moderate Low (<<1 bit/nt)
Noisy storage channels Inference difficulty High Simple High High (≥1 bit/nt)
PCR Unknown primers Low Simple Weak High (≥1 bit/nt)

compared with other techniques, the information density of empirical data, advanced modeling techniques, and in-depth
DNA chips and DNA origami is extremely low (<<1 bit/nt) biological knowledge. Moreover, no standard protocol exists to
because the probes (~30 nt) in each spot only represent one bit test the security of the system under malicious biological attacks.
of information. Therefore, a quantitative measure of these complexities is neces-
Although various DNA cryptography methods have been sary to guarantee the security and efficiency of the system and
proposed by researchers, they are far from being practically to boost the advancement of DNA cryptography.
applied. To develop a solid and reliable cryptographic system Second, a well-established protocol (e.g., key generation,
that is compatible with biological technologies, there are several distribution, and management) has not yet been developed in
main challenges, as follows: DNA cryptography, which hinders its application in practical
First, it is difficult to quantify the biological difficulties inher- scenarios. Conventional cryptography has developed a set of
ent in biochemical reactions, which form the essential basis for standard protocols and algorithms, such as substitution, per-
DNA cryptography. The overall complexity is a function of the mutation, confusion, diffusion, and encryption/decryption
number of biochemical reaction steps (n), the variability of algorithms, which form the foundation for various symmetric
reaction conditions (V), the uncertainty in enzyme kinetics (U), encryption algorithms, such as AES and DES. To achieve reli-
and the influence of external biological factors (F). Variations able data encryption, we should also construct biologically
in reaction conditions can considerably impact the outcome as compatible protocols in DNA cryptography.
these factors are highly interrelated. Quantifying and determin- Third, the unique IDS noise in DNA storage can consider-
ing the exact functional relationship require a combination of ably impact DNA encryption. DNA encoding and PCR both

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code at the base level, making them susceptible to IDS noise. Competing interests: The authors declare that they have no
This noise may disrupt the encryption process, complicate key competing interests.
management, reduce operational efficiency, and increase vul-
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