1
Nucleoside-based sup amolecula hyd ogels: om 1
syn hesis and s uc u al p ope ies o biomedical and 2
issue enginee ing applica ions 3
Ma ia Godoy-Galla do†,*, Ma ia Me ino-Gómez†, Luisama ia C. Ma iz†, Miguel A. Ma eos-4
Timoneda†, F. Ja ie Gil†,§, Roman A. Pe ez†,* 5
†Bioenginee ing Ins i u e o Technology (BIT), Depa men o Basic Science, In e na ional 6
Uni e si y o Ca alonia (UIC), Ca e de Josep T ue a, 08195, San Cuga del Vallès, Ba celona, 7
Spain 8
§Depa men o Den is y, Facul y o Den is y, In e na ional Uni e si y o Ca alonia (UIC), 9
Ca e de Josep T ue a, 08195, San Cuga del Vallès, Ba celona, Spain 10
KEYWORDS. Nucleoside-based hyd ogels, guanosine and de i a i es, sup amolecula hyd ogel, 11
sel -assembly, s abili y imp o emen , enhancemen o mechanical p ope ies 12
ABSTRACT. Sup amolecula hyd ogels a e o g ea in e es in issue sca olding, diagnos ics and 13
d ug deli e y due o hei biocompa ibili y and s imuli- esponsi e p ope ies. In pa icula , 14
nucleosides ep esen p omising candida es as building blocks due o hei mani old nonco alen 15
in e ac ions and easiness o chemical modi ica ion. Signi ican p og ess in he ield o e ecen 16
yea s has been made o allow he use o nucleoside-based sup amolecula hyd ogels in he 17
2
biomedical ield, namely d ug deli e y and 3D biop in ing. Fo example, hei long- e m s abili y, 1
p in abili y, unc ionali y, and bio-ac i i y ha e been g ea ly imp o ed by employing mo e han 2
one gela o , inco po a ing di e en ca ions, including sil e o an ibac e ial ac i i y, o addi i es 3
such as bo ic acid o e en biomolecules. This now pe mi s hei use as bioinks o 3D p in ing o 4
p oduce cell-laden sca olds wi h speci ied geome ies and po e sizes, as well as a homogenous 5
dis ibu ion o li ing cells and bioac i e molecules. We ha e summa ized he la es ad ances in 6
nucleoside-based sup amolecula hyd ogels, and we discuss hei syn hesis, s uc u al p ope ies, 7
and po en ial applica ions in issue enginee ing, and p o ide an ou look and u u e pe spec i e on 8
ongoing de elopmen s in he ield. 9
1. INTRODUCTION 10
The de elopmen o ad anced ma e ials o issue egene a ion is a cen al goal in he ield o 11
issue enginee ing. Pa icula a en ion has been paid o he de elopmen o new bioma e ial 12
suppo s capable o espond o bo h in e nal o ex e nal s imuli (e.g. pH, empe a u e, small 13
molecules, enzymes), and exhibi a con olled hos immune esponse a e implan a ion, among 14
o he s.1,2 Among he cu en ly a ailable bioma e ials, hyd ogels, i.e. h ee-dimensional (3D) 15
ne wo ks o hyd ophilic and c oss-linked polyme s, a e o pa icula in e es owing o (i) hei high 16
wa e con en ( ypically 70–99% w/ ) due o capilla y e ec s and su ace ension3; (ii) he 17
possibili y o con e hem wi h s imuli- esponsi e p ope ies; and (iii), hei 3D 18
mic oen i onmen s highly sui able o cell iabili y. 19
Depending on he unde lying c oss-linking mechanism, hyd ogels can be de ined as ei he 20
chemical o physical. Chemical hyd ogels a e c ea ed by co alen bond o ma ion be ween he 21
indi idual polyme chains, and hus hey p o ide a pe manen ma ix ha is only disabled i he 22
3
bonds a e b oken. Fo example, c oss-linking o inyl-sul one- unc ionalized dex an wi h 1
hiola ed poly(e hylene glycol) (PEG) esul s in apid o ma ion o a chemical hyd ogels.4 Physical 2
hyd ogels, on he con a y, ely on non-co alen in e ac ions such as hyd ogen-bonds (H-bonds), 3
an de Waals o ces, columbic in e ac ions, and polyme chain en aglemen .3,5 These in e ac ions 4
educe he lexibili y o he sys em and d i e gela ion, he eby changing he mac oscopic beha io 5
o he o mula ion, culmina ing in he o ma ion o a 3D ne wo k. Two common hyd ogels in he 6
biomedical ield a e polylac ic acid (PLA) and polycap olac one (PCL). Howe e , as hey a e 7
a he hyd ophobic, hey a e ypically combined wi h hyd ophilic polyme s such as PEG o c ea e 8
amphiphilic copolyme s (e.g. PEG-PCL) wi h imp o ed unc ionali y.6 Fo u he de ails on 9
equen ly used non-nucleoside-based hyd ogels, please e e o he ollowing li e a u e.7,8 10
Impo an ly, non-co alen o ces a e e e sible and hus can be modula ed by dis inc s imuli 11
such pH change, o by he addi ion o bioac i e molecules.3,5 Thus, e e sibili y o hyd ogels may 12
be accomplished by e e sible physical in e ac ions (e.g. H-bonds, hyd ophobic sel -assembly and 13
hos -gues in e ac ions) o by dynamic co alen bonds (e.g. imine bonds, bo ona e es e bonds, 14
disulphide bonds, o ia Diels-Alde eac ion).9 15
The ex acellula ma ix (ECM) is an ex ensi e and complex ne wo k o collagen, laminin, 16
elas in, and p o eoglycans. Toge he wi h ca bohyd a es, hey o m a s ong ib ous ma ix ia 17
in e molecula , non-co alen in e ac ions ha go beyond he indi idual molecule. Consequen ly, 18
a ue biomime ic hyd ogel has o exhibi simila sup amolecula in e ac ions as he ECM. In such 19
scena io, sup amolecula hyd ogels ha e o i s o m a he molecula le el by sel -assembly o 20
he componen s, ollowed by he es ablishmen o a c oss-linked ne wo k o non-co alen 21
in e ac ions. Impo an ly, due o he high associa ion and dissocia ion a es o he componen s, 22
hese physical hyd ogels exhibi s ong dynamic beha io .10 Acco ding o hei binding mo i s, 23
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sup amolecula hyd ogels can be p ima ily di ided in o (i) molecula hyd ogels,11,12 (ii) polyme ic 1
sup amolecula hyd ogels,10,13–15 and (iii) hyb id sup amolecula hyd ogels (Figu e 2).16,17 2
Molecula hyd ogels a e ma e ials o med by he hie a chical and non-co alen sel -assembly o 3
low molecula weigh gela o s (LMWG, <3000 Da in molecula weigh ), including a y acids,18 4
suga s,19 choles e ol,20 amino acids,12 pep ides,21 and, mos impo an ly, nucleosides.22 Such 5
hyd ogels ha e a ac ed special in e es due o hei capaci y o o m ib ous ne wo ks mimicking 6
biopolyme ne wo ks by non-co alen associa ion o hei building blocks. Impo an ly, molecula 7
gela ion occu s in h ee hie a chical s eps: (i) he molecula building blocks con e ge o o m one-8
dimensional nuclei; (ii) hese nuclei hen g ow o o m agg ega es and nano ibe s ha can c oss-9
link o en angle ia non-co alen in e ac ions; and (iii), he o med nano ibe s hen sel -assemble 10
o o m a complex 3D mesh and ib illa ne wo k. Thus, he hyd ophilici y and hyd ophobici y o 11
he used gela o s mus be co ec ly balanced o pe mi and egula e he gela ion o sup amolecula 12
hyd ogels. Fo example, oo high hyd ophobici y may lead o p ema u e p ecipi a ion o he 13
hyd ogel o mula ion and a oo low capaci y o he p in ed s uc u e o hold wa e .23,24 Nucleic 14
acids such as nucleobases, nucleosides, and nucleo ides ep esen a ac i e gela o s and building 15
blocks o he syn hesis o hyd ogels due o hei excellen biocompa ibili y and di e se 16
physicochemical p ope ies, which can also be combined in o bina y hyd ogels due o hei sha ed 17
sup amolecula chemis y and in e molecula in e ac ions such as hyd ogen bonds be ween 18
elec on-de icien and elec on- ich a oms.25 19
Polyme ic sup amolecula hyd ogels a e o med by polyme s wi h sup amolecula mo i s, 20
esul ing in hei c osslinking. In he hyb id sup amolecula hyd ogels, nano-s uc u al mo i s a e 21
used along wi h addi ional mul i alen c osslinking si es. 22
5
These sup amolecula hyd ogels can emodel, eshape, and adap o changing en i onmen al 1
condi ions.10 Howe e , while hei dynamic beha io allows hem o be injec ed in o a ge si es 2
o allows cells o sp ead and mig a e, his dynamici y migh dec ease hei mechanical s eng h. 3
Thus, he pe ec balance be ween s abili y and dynamici y mus be es ablished o each po en ial 4
applica ion. 5
The inco po a ion o o hogonal non-co alen in e ac ions in hei syn hesis, such as π-π s acks 6
be ween a oma ic ings, may p o ide a solu ion o his d awback.26–28 These addi ional a ac i e 7
in e ac ions inc ease he s eng h and numbe o connec ions be ween he LMWGs, u he 8
s abilizing he sel -assembled hyd ogel and g ea ly imp o ing i s mechanical p ope ies. Among 9
he a ious hyd ogel sys ems explo ed o da e ha exhibi hese key cha ac e is ics, nucleoside-10
based hyd ogels appea o be he mos p omising as hey p esen a shea modulus and hixo opic 11
p ope ies ha a e highly compa ible wi h ex usion-based 3D p in ing, as hey allow o he 12
embedding o bo h cells and bioac i e molecules, and as hey can ensu e su i al o ex uded cells. 13
Fu he mo e, hei chemis y is simple and non-haza dous, and hei ib illa and highly dynamics 14
ne wo k p o ides a so sca old ha esembles he ex acellula ma ix, and hei mac oscopic 15
elas ic beha io in combina ion wi h luid-like mic o iscosi y p ope ies appea s ideal o cell 16
p oli e a ion and di e en ia ion. 17
Recen s udies ha e shown majo de elopmen s in nucleoside-based hyd ogels, including 18
enhanced he apeu ic pe o mance o d ug deli e y and con olled d ug elease. Fo example, 5′-19
deoxy-5′-iodoguanosine hyd ogels we e used o deli e an i i als,29 and mechano esponsi e 20
hyd ogels based on hymine we e employed o he adminis a ion o an ibodies.30 To u he 21
imp o e d ug e icacy and educe nega i e side e ec s on heal hy cells o issues, injec able 22
nucleoside-based hyd ogels a e being de eloped wi h sus ained and unable local elease o 23

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bioac i e molecules. No ably, hyd ogels ha e been used as so-called ECM-mime ics ha can 1
p o ide a sui able en i onmen o cell su i al and p oli e a ion due o hei esemblance o so 2
issues and simila i y in composi ion o he ECM.31,32 Fu he mo e, such hyd ogels may be 3
p epa ed con aining li ing cells and signaling molecules, u he enhancing sca old in eg a ion 4
and enabling cap u ing cells om ci cula ion.33 Such sup amolecula hyd ogels ha e also been 5
shown o unc ion e ec i ely as sca olds o bone issue enginee ing. Fo ins ance, Maisani e 6
al.34 c ea ed hyd ogels o cell embedding by combining glyco-nucleo-lipids con aining a 7
luo ina ed ca bon chain (GNF) wi h ype I collagen. A e subcu aneous implan a ion, hese 8
sca olds p o ided a a o able en i onmen o long e m cell su i al and p omo ed cell 9
di e en ia ion in o os eoblas s. 10
To summa ize, ideal sup amolecula hyd ogels o issue enginee ing can o m unde chemically 11
mode a e o e en physiological condi ions, and hey can epea edly ansi ion om p ima ily 12
elas ic o p edominan ly iscous p ope ies (shea - hinning), allowing hem o egain hei o iginal 13
shape and iscosi y upon s ess.35 Such sel -healing and e-assembly capabili ies a e c i ical o 14
allowing hyd ogel injec ion a de ec si es and o ensu e minimal in asi eness du ing sca old 15
implan a ion. Mo eo e , ideal hyd ogels should enable encapsula ion o bo h bioac i e compounds 16
and li ing cells in o hei physically c osslinked nano ib illa ne wo k, whe e a high-wa e capaci y 17
and well-de ined po es ensu e cell su i al, p oli e a ion, and di e en ia ion, while also allowing 18
o he ex ended and s eady elease o small molecule compounds such as d ugs in o he 19
en i onmen , he eby augmen ing such sca olds (e.g.) wi h an i-in lamma o y and/o an i-20
bac e ial p ope ies o imp o e implan e ec i eness and minimize chances o ejec ion.36 Finally, 21
ideal hyd ogels would enable uneable d ug elease, o example by s imuli- esponsi e 22
capabili ies, allowing hei use as biosenso s du ing issue epai (Figu e 1). 23
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This e iew ocuses on he mos ecen ad ances and de elopmen s in nucleoside-de i ed 1
sup amolecula hyd ogels, wi h a pa icula emphasis on he physicochemical p ope ies impo an 2
in issue enginee ing and egene a i e medicine. Wi h a ocus on nucleoside-based hyd ogels, we 3
discuss po en ial applica ions o di e en o mula ions as bioma e ial inks, injec able hyd ogels, 4
and cell-laden bioinks. In Table 1, a summa y o he mos impo an p ope ies and applica ions o 5
nucleoside hyd ogels is p o ided. We also add ess he need o de eloping and implemen ing 6
common quan i a i e me ics in he ield o assu e s udy compa abili y, as well as ou line u u e 7
esea ch di ec ions and po en ial medical applica ions o nucleoside-based hyd ogel ma e ials. 8
2. NUCLEOSIDE-BASED SUPRAMOLECULAR HYDROGELS 9
Nucleosides a e a class o biomolecules composed o a combina ion o a nucleobase 10
(ni ogenous base) and a suga ing. Nucleobases a e g ouped in o wo majo o ms: pu ines and 11
py imidines (Figu e 3Ai). While bo h a e he e ocyclic a oma ic compounds, hey di e ge in hei 12
chemical s uc u e. Pu ines consis o a bicyclic s uc u e wi h many po en ial H-bond in e ac ion 13
si es, while py imidines ha e only one ca bon ni ogen ing wi h h ee hyd ogen dono and 14
accep o si es.3 15
The abili y o hese building blocks o o m sup amolecula s uc u es is imp in ed on hei 16
molecula le el and hei in insic p ope ies such as p o on a ini ies, hyd ogen bonding and π- π 17
s acking capabili ies, and he p ope balance o hyd ophobici y and hyd ophilici y. Ni ogenous 18
bases, o example, can o m sup amolecula assemblies by o ming H-bonds and π-π s ack 19
in e ac ions, which a e c i ical o con olling he 3D s uc u e o DNA and RNA assemblies.3,37 20
Mo eo e , hey a e equen ly used as sup amolecula building blocks o c ea e mo e complex 21
s uc u es wi h hixo opic (i.e., displaying a iscosi y ha lowe s when s ess is applied) and sel -22
healing capabili ies, all while main aining a good en i onmen o cell iabili y. Nucleobases ha e 23
8
go en a lo o in e es la ely because o hei excep ional abili y o gene a e in e molecula 1
in e ac ions in aqueous solu ions and hei use as building blocks o hyd ogela o s.38–40 2
Nucleobases eadily engage in e e sible in e ac ions, and can o m bo h homodime s and 3
he e odime s wi h o he nucleobases. No ably, all i e nucleobases, namely adenine (Ade), 4
cy osine (Cy ), guanine (Gua), hymine (Thy), and u acil (U a) can o m di e en enla ged 5
s uc u es depending on he condi ions, such as ibbons—a plane held oge he by eigh hyd ogen 6
bonds, o quad uplexes, a seconda y s uc u e wi h a cen al e ad ha can be u he s abilized by 7
he p esence o a ca ion like po assium (K+). The esul ing dense ne wo k o physical in e ac ions 8
no only in e s hyd ogel s abili y, bu also s uc u al e sa ili y, uneabili y, and sel -healing 9
capaci y, all key pa ame e s o hyd ogels o issue enginee ing.41–43 10
Likewise, he ibose pa o nucleosides can also play an impo an ole in he o ma ion o 11
sup amolecula s uc u es and hus con ibu e o hei s abiliza ion. Fo example, nucleo ides 12
possess an anionic phospha e a ached o he ibose ing ha inc eases he s eng h o elec os a ic 13
in e ac ions (Figu e 3Aii).44,45 Baldassa i and co-wo ke s46 s udied he o ma ion o hyd ogels by 14
guanosine 5’-monophospha e (5-GMP). The au ho s p oposed ha in he absence o ex e nal 15
ca ions, only he p esence o 5-GMP monome was de ec ed, while he addi ion o ca ions (in 16
pa icula K+) p o oked he sel -assembly o he building blocks. Addi ionally, S eeni asacha y 17
and Lehn47 desc ibed he guanosine hyd azide as a powe ul hyd ogela o ia he o ma ion o 18
e e sible acylhyd azone bonds a e condensa ion wi h a ious aldehyde compounds, hus 19
c ea ing dynamic lib a ies o acylhyd azones. As a esul , he gela ion p ocess led o a mul ile el 20
sel -assembly o guanosine acylhyd azone de i a i es in o guanosine qua e s (G-qua e s). 21
2.1. Thymidine-based sup amolecula hyd ogels. While a numbe o nucleoside-based 22
hyd ogels ha e been de eloped o e ecen yea s, only a ew s udies ha e ocused on 23
9
sup amolecula gels based on hymidine (Thd). Fo example, Yu e al.48 epo ed a bina y hyd ogel 1
based on Thd and melamine as a gelling componen ha o med a sup amolecula complex gel ia 2
H-bonds and π-π s acking in e ac ions (Figu e 4A). Du ing he gene a ion o he hyd ogel, bo h 3
building blocks co-assemble in o agg ega es, and depending on he a io o Thd o melamine, he 4
backbone o ms shi om od o shee o cu led slices, co ela ing wi h he amoun o ee -NH 5
g oups. As a esul , he au ho s we e able o adjus he gela ion p ope ies and hus hyd ogel 6
s abili y. These unable changes in mo phology allow he o ma ion o nano ubula s uc u es, 7
which migh be exploi ed o make ib illa y sel -assembled sca olds. 8
Following his s udy, Ramin and colleagues49 used Thd as a basic building block o c ea e a 9
s able sup amolecula hyd ogel by combining i wi h 1,2-dipalmi oyl-sn-glyce ol phospha e 10
(diC16dT) and a ious mono alen ions such as li hium (Li+), sodium (Na+), K+, ammonium 11
(NH4+) and ie hyl ammonium (E 3NH+) (Figu e 4B). Expe imen s pe o med by ansmission 12
elec on mic oscopy (TEM) e ealed ha nano ib illa s uc u es we e only ound in diC16dT/Li+, 13
diC16dT/Na+ and diC16dT/K+, while lamella s uc u es we e ob ained in diC16dT/NH4+ and 14
diC16dT/E 3NH+. These esul s sugges ha la ge ca ions can impac he sup amolecula 15
o ganiza ion o he ne wo k. Mo eo e , hese hyd ogels possessed p ope hixo opic and 16
heological p ope ies, allowing hei use in injec ion-based applica ions such as 3D p in ing. 17
2.2. Cy idine-based sup amolecula hyd ogels. Cy idine (Cyd) nucleoside is ano he LMWGs 18
based on he Cy nucleobase and a i e-ca bon suga ibose wi h hyd ogen-bonding dono s and 19
accep o s which a e necessa y o induce gela ion.50,51 Howe e , despi e he ac ha Cyd has 20
in iguing cha ac e is ics like he capaci y o bind o sil e (Ag+), which could gi e he hyd ogel 21
an ibac e ial p ope ies, ew s udies ha e been epo ed on i s po en ial as a gela o .52,53 This may 22
be explained by ha ing one ewe hyd ogen accep o /dono g oup han guanosine (5 s. 6), which 23
16
especially o issue enginee ing.23,81,82 Impo an ly, because o he addi ional hyd ogen-bonding 1
edges and i s abili y o c ea e π–π s acks, guanine has he highes sel -assembly capabili y o he 2
i e nucleobases. 3
2.5.1. Guanosine de i a i es hyd ogels. To modula e he p ope ies o G4 hyd ogels, se e al 4
s udies ha e sugges ed ha he 5’-OH in he Guo is no impo an o he gela ion, hus se e al 5
e o s ha e cen e ed on 5’-modi ied guanosines, such as 5′-monophospha e,83–85 5’-hyd azides47 6
and 5’-OAc.86 Belda e al.87 s udied he sel -assembly o 5-GMP-de i a i es using polyamines o 7
inc ease he s abili y o he 3D ma ix. The esul s showed an inc ease o he gela ion e iciency 8
when polyamines we e used, and i was possible o educe he 5-GMP concen a ion. Addi ionally, 9
Taylo e al.29 designed a sel -des oying G4 hyd ogel based on he sel -assembly o bo a e es e s 10
o 5-deoxy-5-iodoguanosine (5-IG). The au ho s hypo hesized ha he inco po a ion o he iodo 11
g oup (I) (a good lea ing g oup) a C5’ o he ibose ing would acili a e he in amolecula 12
cycliza ion by N3. This may dis up he in eg al s uc u e o he gel since he newly o med bond 13
is incompa ible wi h he G-qua e subs uc u e. The esul s demons a ed ha he in si u 14
in amolecula cycliza ion is empe a u e-sensi i e and can occu e en a e gel o ma ion, he eby 15
inducing “sel -des uc ion”. Simila sys ems could be used as d ug deli e y ca ie s capable o 16
unloading hei ca go in esponse o an ex e nal s imulus. 17
To add ess he low li e ime o Guo-based hyd ogels, a se ies o s udies ocused on p epa ing 18
isoguanosine (isoGuo) hyd ogels. IsoGuo is an isome o Guo wi h an exchange o he subs i uen s 19
a C2 and C6 (Figu e 7A).88 Zhao e al.88 s udied he hyd ogel o ma ion by using isoGuo combined 20
wi h low concen a ions o alkali me al ions. Compa ed o p e ious Guo-based hyd ogels, which 21
collapsed wi hin minu es o hou s, hese de i a i e s uc u es showed long- e m s abili y o up o 22
se e al mon hs. This was explained by he ac ha isoGuo p o ides addi ional dono and accep o 23

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g oups o he ou e shell hyd ogen-bond in e ac ions. The au ho s concluded ha he o med 1
e aplexes and pen aplexes we e piled up o o m agg ega es, while he ou e shell H-bonds 2
p o oked he ibbon-like in e ac ion wi h o he isoGuo compounds. Scanning elec on mic oscopy 3
(SEM) demons a ed ha isoGuo hyd ogels o med in e connec ed helical ibe s and ha , unde 4
physiological condi ions, he gel showed long- e m s abili y and exhibi ed g ea loading and 5
elease p ope ies o small-molecule compounds. In pa icula , he au ho s encapsula ed a ca ionic 6
and a oma ic dye, namely me hylene blue (MB), in he isoGuo hyd ogel, showing a ela i ely as 7
elease o ~40% in he i s 4 h. Then, he emaining MB was eleased slowly, leading o 8
equilib ium a e 26 h. The e o e, he use o he isoGuo biological ac i i y oge he wi h i s gel-9
o ming p ope ies may be especially use ul in he con ex o d ug deli e y applica ions o o he 10
cons uc ion o nanoscopic de ices. 11
Thaku e al.89 de eloped a dual c oss-linked G4 hyd ogel capable o con olling he deli e y o 12
doxo ubicin (Dox), a po en an icance d ug. In pa icula , he au ho s o med a G4 hyd ogel by 13
c oss-linking he G4 o he nucleo ide 5-GMP h ough in e ac ions be ween he phospha e g oups 14
and hyd olyzed i on (III) ions (Fe3+). Finally, he hyd ogels we e c oss-linked h ough calcium ion 15
(Ca2+) by b idging he diol g oups o he ibose moie y o 5-GMP. In an in i o s udy o 20 days, 16
he esul ing hyd ogel showed a pH- esponsi e elease o doxo ubicin. Fo ha , he au ho s 17
imme sed he hyd ogels in phospha e bu e ed saline (PBS) (10 mM, pH 4.0, 5.5, and 7.4) and a 18
di e en ime poin s, he PBS bu e was emo ed o analysis, and eplaced wi h esh bu e . 19
A e 20 days, only 3% o Dox was eleased a pH 7.4, sugges ing high s abili y o he gel. 20
Howe e , a pH 4, a much as e elease was obse ed (90% a day 20), demons a ing he acid-21
esponsi e beha io o he hyd ogel. Due o his esponsi eness o an ex e nal s imulus and i s 22
cons an a e o d ug elease, hese hyd ogels migh enhance he e sa ili y o d ug deli e y 23
18
sys ems. An impo an limi a ion o Guo-based hyd ogels is due o he po en ial c ys alliza ion o 1
he gel s uc u e, which can happen wi hin hou s a oom empe a u e and s ongly impac s hei 2
s abili y, as he gels a e ende ed b i le and lose hei lexible o e all s uc u e. Feng e al.90 3
de ailed he c ys alliza ion mechanism o a 2’-deoxy-2’- luo oguanosine (FGd) hyd ogel in o de 4
o unde s and he balance be ween gela ion and c ys alliza ion. The au ho s con i med ha he 5
addi ion o K+ in o he G-qua e acili a ed he o ma ion o a linea ibbon s uc u e, and hey 6
sugges ed ha i may be ela ed o he endency o Guo-based hyd ogels o c ys allize. 7
2.5.2. Bina y hyd ogels o guanosine wi h o he de i a i es. A numbe o bina y hyd ogels 8
cons i u ed by Guo and one o i s de i a i es ha e been ecen ly assessed in o de o inc ease hei 9
li e ime s abili y and physical p ope ies.91,92 Among hem, he mix u e o he hyd ophobic Guo 10
and he hyd ophilic 5-GMP was able o o m s able and anspa en hyd ogels in wa e . Guo is 11
cha ac e ized as an insoluble nucleoside ha can o m s able hyd ogels e en a high sal 12
concen a ions. On he o he hand, 5-GMP is highly soluble a neu al pH bu i s gela ion is highly 13
concen a ion dependen . Hence, 5-GMP imp o es he solubili y o Guo, and he insolubili y o 14
Guo endo ses he gela ion o 5-GMP a lowe concen a ions. Ca ducci e al.93, o example, 15
desc ibed a bina y mix u e o Guo and 5-GMP capable o o ming a anspa en hyd ogel in he 16
p esence o K+. Nex , Na as e al.82 combined Guo and 5-GMP in o de o ob ain a wo-compound 17
hyd ogel and o s udy he mechanism causing he gela ion o he solu ion. The au ho s desc ibed 18
a nano-pa i ioning o he mix u e whe e he 5-GMP- ich egion o ms la ge columns o G-qua e s 19
while he Guo- ich a eas showed kno ed coils o G4. The Guo- ich angles o med he nodes o 20
he ne wo k and we e linked h ough he he mally e e sible 5-GMP- ich ib es. La e , Yoneda 21
e al.94 s udied he encapsula ion and elease o key p o eins om he hyd ogel using MB as a 22
pho osensi ize (Figu e 7Bi). They employed a combina ion o Guo and 5-GMP and loaded he 23
19
hyd ogel wi h MB a a inal concen a ion o 50 mg mL-1. Thei analysis e ealed a hyd ogel wi h 1
good mechanical p ope ies ha had no cy o oxic e ec s on cells when seeded on o he ma ix. 2
Mo eo e , he MB elease s udy sugges ed a mechanism dependen on he hyd ogel composi ion. 3
Fo example, he elease o MB a e he i s 8 h was highes when he a io o Guo- o-5-GMP 4
was 1:6 (57%), ollowed by 1:2 (46%) and inally 1:1 (31%) (Figu e 7Bii). Howe e , a e 24 h, 5
he MB elease om he 1:6 a io was he lowes . This was explained by he ac ha hese 6
hyd ogels had he highes amoun o nega i e cha ge in he hyd ogel (due o he highes 7
concen a ion o 5-GMP), and his may ha e seques e ed some basic le els o MB molecules due 8
o hei posi i e cha ge. And impo an ly, i has been demons a ed ha bina y hyd ogels o Guo-9
o-5-GMP may be employed as bioma e ials o biomolecule encapsula ion. 10
While isoGuo is capable o o m s able hyd ogels, i exhibi s poo injec abili y due o insu icien 11
s eng h a e injec ion, limi ing i s applicabili y in issue enginee ing applica ions. Taking his in o 12
accoun as well as he p ope ies o Guo o gene a ing G-quad uplex hyd ogels, Tang e al.56 13
e alua ed he u iliza ion o Guo and isoGuo in he p esence o ca ions o o m a wo-componen 14
co-gel. The esul s showed ha a sel -healing nucleoside hyd ogel con aining K+ may be c ea ed. 15
SEM images e ealed a lowe -like mo phology and e idenced he p esence o some c oss-linking 16
be ween Guo and isoGuo (Figu e 7C). Injec ion expe imen s u he demons a ed ha he co-gel 17
had a quick eco e y ime and o e all injec able p ope ies. Finally, isoGuo is conside ed as a 18
molecule wi h an i umo ac i i y.95 As a esul , his wo-componen co-gel has he po en ial o be 19
e ec i e no only in issue egene a ion bu also in an icance he apy. 20
2.5.3. Inco po a ion o di e en ionic species in guanosine hyd ogels. To a oid de imen al 21
c ys alliza ion, Feng and colleagues90 p oposed ha s onge me al bonds (e.g. pla inum ion (P 2+), 22
me cu y ion (Hg2+) o Ag+ could be a p omising al e na i e due o he o ma ion o a me al ion-23
20
linked and H-bonded s uc u e by coo dina ion wi h he elec on- ich ni ogen and oxygen g oups 1
om he su ounding he e ocyclic pu ine ings. Hence, he FGd hyd ogel was p epa ed in he 2
p esence o sil e ions and he eby demons a ed a emendously inc eased li e ime s abili y o up 3
o 6 mon hs (Figu e 7Di and ii). Fu he mo e, he use o sil e ions in he hyd ogel o ma ion may 4
p o ide an ibac e ial p ope ies o he ne wo k, making applica ions in wound healing a logical i 5
(Figu e 7Diii). 6
Simila ly, ecen s udies suppo he idea ha lan hanides o i alen ions can induce Guo 7
gela ion.89,96 Zhang e al.97 used 5-GMP as building blocks o achie e gela ion ia G-quad uplex 8
o ma ion in aqueous solu ion by he use o lan hanide ions, such as lan hanum (La3+), ce ium 9
(Ce3+), eu opium (Eu3+) and e bium (Tb3+). The esul s showed an inc ease in he s abili y o he 10
G4 hyd ogels when lan hanide ions we e used ins ead o he adi ionally used mono alen ca ions. 11
The TEM images showed a dense a angemen o nano ibe s induced by La3+ and Ce3+ compa ed 12
o Eu3+ and Tb3+, which displayed sho nano ibe s o c owded clus e s. These dis inc 13
mic os uc u es we e co ela ed wi h he mechanical s eng h o he hyd ogel, eaching i s highes 14
when La3+ was used a a concen a ion o 12 mM. The au ho s associa ed his e ec wi h he 15
in e ac ion deg ee o he La3+ wi h he G-qua e s ia ion-dipole in e ac ion, which a ec s he 16
gela ion p ope ies o he gels. 17
To da e, a numbe o s udies ha e been pe o med o examine Guo-based hyd ogels o med wi h 18
di alen ca ions (M2+) ins ead o adi ional alkali me als.23,98,99 Al hough he majo i y o hese 19
s udies ocused on hyd ogels o en i onmen al pu poses, Plank and colleagues80 hypo hesized 20
ha he g ea e cha ge densi y gi en by M2+ would imp o e he elec os a ic in e ac ions wi h he 21
anionic gela o s. In pa icula , hey s udied he o ma ion o s able and anspa en Guo hyd ogels 22
21
using di e en di alen ca ions such as ba ium (Ba2+), s on ium (S 2+) and lead (Pb2+) by mixing 1
Guo wi h 8-aminoguanosine (8AmG). 2
2.5.4. Guanosine hyd ogels wi h bo ic acid and i s de i a i es. In ecen yea s, bo onic acids 3
(BAs) ha e become a powe ul addi ion o imp o e he s abili y o G4 sup amolecula hyd ogels. 4
Pe e s e al.39 desc ibed a Guo-based hyd ogel whe e he igh combina ion o bo a e anions and 5
K+ was c ucial o gela ion and s abili y. A e combining Guo, po assium hyd oxide and bo ic 6
acid, a guanosine-bo a e (GB) hyd ogel wi h excellen li e ime p ope ies was ob ained. The 7
au ho s hypo hesized ha a single bo a e anion is able o eac wi h Guo in o de o o m co alen 8
Guo dime s ha ac as building blocks in he sup amolecula ne wo k whe e he GB dies e s 9
acili a e he sel -assembly o G4-K+ hus he o ma ion o s able hyd ogels. The same esea ch 10
g oup subsequen ly p o ided u he insigh s in o he mechanism o GB hyd ogel o ma ion by 11
s udying how he indi idual componen s (e.g. bo a e sal , GB dies e s o G-qua e s) de e mine he 12
s uc u e and p ope ies o he inal GB hyd ogels.55 Fo example, he au ho s obse ed ha he 13
addi ion o K+ ga e he s onges GB hyd ogel in compa ison o Li+. By he luo escence esponse 14
o hio la in-T (ThT), a dye ha selec i ely binds o he G-qua e , he au ho s obse ed he la ges 15
luo escen signal when K+ was used o gel o ma ion (Figu e 8A). The au ho s hypo hesized ha 16
his was due o inc eased and mo e obus G-qua e gene a ion in he p esence o K+, as e idenced 17
by he inc eased numbe o ThT binding si es. The esul s showed ha he ca ions' impo ance 18
elies on he s abili y o he anionic dies e s and he G-qua e uni s, ha a e he eal building blocks 19
o he sup amolecula hyd ogel. The esul s showed ha he ype o ca ion s ongly impac s he 20
s abili y o he GB dies e and G-qua e and, hus, as he la e ep esen he c ucial building block 21
o he gel, he p ope ies o he sup amolecula hyd ogel. 22

22
Inspi ed by he use o bo ona e compounds o hyd ogel s abili y, Qiao e al.100 desc ibed he 1
gene a ion o a GB-based hyd ogel by he combina ion o Guo and 2- o mylbo onic acid (2-FPBA) 2
in he p esence o po assium hyd oxide (KOH). In iguingly, he au ho s epo ed di icul ies in 3
o ming a sel -suppo ing gel when alkali me al ions we e used ins ead o K+. In 2020, Ghosh and 4
co-wo ke s101 epo ed he use o 1-naph halenebo onic acid (NapBA) o o m a Guo-based 5
hyd ogel. As shown by luo escence and ci cula dich oism (CD), he gene a ion o G4 s uc u es 6
was disc imina ing owa ds K+ ions (Figu e 8B) Mo eo e , a e he e alua ion o he 7
biocompa ibili y o he hyd ogel by in i o cy o oxici y, he au ho s s udied he quan i a i e and 8
con olled elease o i amin B2 and i amin B12. The esul s showed a highe elease a e o 9
i amin B2 han i amin B12 (60% and 30% o he i s 40 h, espec i ely), p obably due o he 10
nea ly 4- imes la ge molecula weigh o i amin B12. Thus, he au ho s could clea ly demons a e 11
ha hese hyd ogels a e no only use ul o issue enginee ing bu also o con olled d ug deli e y. 12
The mul iple and dynamic in e ac ions in he sup amolecula ne wo k allow he hyd ogel o 13
espond o a ious s imuli such as hea , pH, glucose, and hyd ogen pe oxide. Li e al.79, o 14
example, epo ed a s imuli-sensi i e GB hyd ogel composed o Guo, 2-FPBA, is(2-15
aminoe hyl)amine (TAEA) and a K+ co e. The 2-FPBA was added o he ne wo k bo h o enhance 16
hyd ogel o ma ion and o p o ide a con olled b eaking poin upon inducible and dynamic 17
in e ac ions unde pH changes and saccha ide s uc u e in e ac ions. Addi ionally, Hu e al. 77 18
de ailed a mul i-s imuli esponsi e hyd ogel consis ing o Guo, K+, 2-FPBA and aminoglycoside. 19
No ably, aminoglycosides p esen po en b oad-spec um an ibio ic ac ion. In his s udy, he 20
au ho s ound ha hey also ac as good hyd ogel gela o s, po en ially acili a ing an ibac e ial 21
wound pa ches o he ea men o bac e ial in ec ions.In 2020, Biswas e al.102 epo ed he 22
p epa a ion o a dynamic GB hyd ogel by combining Guo, 2-FPBA and 4-A m PEG-NH2, a 23
23
mul ia m PEG de i a i e wi h e minal amine g oups and a pen ae y h i ol co e. The au ho s 1
hypo hesized ha he imine bonds ac ed as a connec o be ween he PEG and he G-qua e uni s, 2
esul ing in a highly in e wined dynamic ne wo k and a G4 s uc u e, which was con i med by 3
ThT binding. When ThT was added o he GB hyd ogel, i became luo escen and showed a 4
dis inc emission peak a 560 nm (λex = 450 nm), which was caused by he π-π s acking in e ac ions 5
be ween ThT and he G4 s uc u e. Addi ionally, a sel -healing es was conduc ed by connec ing 6
h ee pieces whe e only he ex e nal ones we e ea ed wi h ThT. The esul s showed a g adual 7
di usion h ough he connec ing join s, and a e 2 h, a used hyd ogel block was obse ed. 8
Finally, he au ho s inco po a ed he an icance d ug doxo ubicin hyd ochlo ide and moni o ed he 9
ime-dependen d ug elease. Upon shi ing he pH o 4.8, he acid-labile imino-bo ona e bonds 10
we e b oken, leading o he des abiliza ion o he hyd ogel nano ibe s and, consequen ly, he 11
elease o he embedded d ug. This s udy elegan ly demons a ed he use o hese s imuli-12
esponsi e hyd ogels as a p omising s a egy o cance he apy. 13
Di e en app oaches ha e been explo ed o cons uc mul icomponen GB hyd ogels by adding 14
addi ional small molecules, especially di alen ions. Ro a u e al.74 p epa ed G-qua e hyd ogels 15
by combining Guo wi h benzene-1,4-dibo onic acid (BDBA) using bo h K+ and Ba2+ ions, and 16
hen u he aiding c oss-linking wi h magnesium (Mg2+) ions. The esul ing hyd ogel showed 17
inc eased s abili y and was able o sus ain highe wa e e en ion, which imp o ed he cell g ow h 18
p ope ies. Cell g ow h and iabili y es s we e pe o med using no mal human de mal ib oblas s 19
(NHDF) and seeding hem on o he hyd ogel. Cells showed a iabili y o up o 73% a e 24 h. 20
Wu and colleagues22 s udied he inco po a ion o he an i i al d ug acyclo i (Ac ) and he 21
loading o he an i-cance d ug me ho exa e (MTX) in a GB hyd ogel using Na+ o G-qua e 22
o ma ion, and hey we e able o ob ain homogeneous MTX/GB and Ac /GB hyd ogels, 23
24
espec i ely. 1H-NMR analysis e ealed ha Ac had been inse ed in o he G4-qua e s uc u e 1
and had eplaced Guo molecules. Mo eo e , CD measu emen s demons a ed ha Ac educed 2
he in e ac ion s eng h be ween he bo ic acid es e and he Guo ibe s, leading o a weakened 3
hyd ogel wi h lowe mechanical s eng h. Due o he esponsi e p ope ies o GB hyd ogels o 4
e.g., glucose and pH, he induced elease o Ac and MTX was moni o ed. MTX exhibi ed an 5
ini ial bu s ollowed by a slow elease. Due o he lack o in e ac ion be ween he MTX and he 6
hyd ogel, he s eng h o elease solely depended on he in ensi y o he ex e nal s imulus (pH, 7
glucose and Na+ concen a ion). Howe e , as Ac was pa o he G4-qua e , he ini ial elease 8
was much lowe compa ed o MTX, and unde all condi ions es ed, he o al elease o MTX was 9
highe han Ac . The e o e, by adding moie ies o d ugs ha a e able o in e ac wi h he G-10
qua e s, he elease a e o he d ug may be al e ed and con olled, allowing he encapsula ion o 11
dis inc biomolecules a he same ime bu wi h di e en elease p o iles. 12
2.5.5. Inco po a ion o compounds in guanosine hyd ogels. The de elopmen o hyd ogels o 13
as e issue egene a ion is o he u mos impo ance, and one key app oach is o inco po a e 14
unc ional agen s in o he ma ix. Fo example, Xiao e al.75 epo ed he inco po a ion o 15
ecombinan human collagen (RHC) in o G4 hyd ogels o c ea ing medical pa ches o wound 16
epai . The au ho s pos ula ed ha he lexible G4-RHC hyd ogel does no only co e he wound, 17
bu eleases he en apped RHC, he eby ec ui ing mac ophages and ib oblas s, and hus 18
accele a ing he epi helial egene a ion (Figu e 8Ci). In i o s udies showed ha he lexible RHC-19
G4 hyd ogel was mo e e ec i e han aga ose -based pa ches o s imula e wound healing. Fo 20
example, a e 7 days o ea men , he wound a ea was abou 91% sealed wi h he RCH-G4 pa ch 21
while only 86% wound closu e was ob ained o he aga ose con ol g oup (Figu e 8Cii). 22
25
Recen ly, Li e al.103 p oposed and demons a ed ha he ca ionic su ac an 1
ce yl ime hylammonium b omide (CTAB) could p omo e he o ma ion o G4 gels. In pa icula , 2
CTAB in e ac s wi h nucleo ides, such as 5-GMP, helping o o m and modula e he ansi ion o 3
G-quad uplex s uc u es. This po en ially g oundb eaking inding opens up new possibili ies o 4
ine- uning unc ional ma e ials ha a e based on G4 assemblies. 5
2.6. He e o ypic nucleoside-based sup amolecula hyd ogels. The majo i y o hyd ogels a e 6
gene a ed by using a single gela o , bu hyd ogels composed o wo o mo e sup amolecula 7
building blocks may show ce ain bene i s, such as a g ea e deg ee o adap abili y.104 Wang and 8
co-wo ke s105 s udied he gela ion o bis-qua e na y ammonium gemini su ac an wi h 5’-u idine 9
monophospha e (5-UMP). The esul s showed ha he gela ion o he mix u e did no occu a a 10
concen a ion o 10 mM o he complex, bu he addi ion o an equimola amoun o Ado u ned 11
he solu ion in o a sup amolecula hyd ogel. The au ho s p oposed ha he hyd ogela ion was due 12
o he o ma ion o H-bonds be ween 5-UMP and he Ado by hyd ophobic in e ac ions be ween 13
he nucleobases. Impo an ly, such a molecula ecogni ion ool esul ing in hyd ogel o ma ion 14
migh show g ea p omise and applicabili y o biosenso s. 15
In gene al, hyd ogels con ain a high amoun o wa e , which p oduces weak bu signi ican 16
adhesion be ween he hyd ogel and solid su aces. Impo an ly, adhesi e hyd ogels ha e p o en 17
b oad applicabili y in issue enginee ing; o example, hey a e used in elec onic de ices o he 18
human body,106 o epai damaged issues,107 in he 3D p in ing o issues108, and as bio-glue.109 19
Liu e al.110 p esen ed a hyd ogel composed o ac yla ed adenine and ac yla ed hymine. The 20
adhesion be ween he hyd ogel and he solid subs a e was imp o ed by he p esence o A and T, 21
and he e o e, he gene a ion o s uc u es ia H-bonds, me al-complexa ion, and hyd ophobic 22
in e ac ion be ween he nucleobases wi h he compounds o he solid. In pa icula , A and T we e 23
32
showed a se o ibe s wi h a hickness o be ween 50 and 100 µm (Figu e 10C). Fo cell iabili y 1
s udies, cells we e inco po a ed in o he hyd ogel by mixing wi h a 39 °C p ehea ed gel. The 2
p in ed cell-laden hyd ogel had a low cy o oxic e ec on human gingi al ib oblas s (HGFs, 93.5% 3
iabili y on day 1) bu a sligh ly highe cy o oxici y on s em cells om he apical papilla (SCAPs, 4
70.5%) (Figu e 10D). The au ho s con i med p e ious esul s ha showed ha HGFs and SCAPs 5
we e esis an o shea s ess and p essu e du ing he ex usion p ocess. The educed SCAP 6
iabili y was a ibu ed o he highe agili y o he s em cells, complica ing hei abili y o su i e, 7
especially in he cen e o he p in ed samples. Impo an ly, he in i o s udy did no show any 8
e idence o in lamma ion, demons a ing he high in i o ole ance o he p in ed sca old. Based 9
on hese esul s, we an icipa e ha his and o he LMW hyd ogels will be employed as cus omized 10
implan s o so issue econs uc ions, which, o he bes o ou knowledge, has no been 11
a emp ed so a . 12
O e he las yea s, impo an ad ances ha e been achie ed, including he o mula ion o hyb id 13
mul icomponen hyd ogels, and cell-laden Guo-based hyd ogels showing g ea po en ial as a 14
pla o m o issue egene a ion. Howe e , s a egies need o be de eloped o imp o e he cell 15
iabili y o he encapsula ed cells and o gua an ee hei p o ec ion du ing he p in ing p ocess. 16
This could be achie ed by p o iding imp o ed iscoelas ic p ope ies o he hyd ogel, which 17
would allow he app op ia e luidi y in he nozzle o ensu e cell p o ec ion. Addi ionally, as he 18
ield e ol es, we expec ha he numbe o applica ions en apping addi ional biomolecules o, 19
e.g., s imula e ascula ne wo k o ma ion in he 3D cons uc s will inc ease. 20
Un o una ely, many ex usion-based (bio)p in ing echniques exhibi insu icien p in ing 21
accu acy o allow a p ope e alua ion o he p in abili y o he (bio)ink. Fu he mo e, many s udies 22
ei he do no e alua e o me ely es he p in abili y o hei new (bio)inks, o assess i only in a 23

33
poo quali a i e manne . Impo an ly, i s e o s ha e been made and p elimina y measu es ha e 1
been es ablished in he ield o de e mine, o example, shape ideli y, p in ing accu acy, and 2
ex udabili y o new ma e ials in a mo e quan i a i e way. Howe e , each o hese echniques 3
e alua es he (bio)ink in a unique way, making compa ison di icul , and many s udies s ill ely on 4
me hods wi h ew o no measu able me ics. Simila ly, desc ip i e e ms such as “p in abili y” 5
equi e a be e and b oadly accep ed de ini ion, and quali y con ol p ocedu es need o be 6
s anda dized o imp o e compa abili y. 7
Fu he mo e, compu a ional p edic ion and simula ion app oaches ha e gained momen um in he 8
las decade since hey can help us o comp ehend he unde lying sel -assembly p ope ies and hus 9
o enhance he pe o mance o sup amolecula hyd ogels.129,130 Such compu a ional echniques can 10
also p o ide in o ma ion on ime poin s and scales o he gela ion p ocess ha expe imen al 11
me hods canno easily p o ide, allowing us o ob ain a mo e comple e pic u e o he p ocess, 12
especially when mul iple compu a ional me hods a e combined and a a ie y o models wi h 13
a ying le els o esolu ion and complexi y (mul iscale modelling) a e used.131,132 In pa icula , 14
he use o machine lea ning 133–135 and AI-based p edic ion ools136,137 will signi ican ly accele a e 15
he de elopmen o applica ion- ailo ed sup amolecula hyd ogels since po en ial gela o s can be 16
i s ho oughly assessed in silico be o e ad ancing in o expe imen al ials. Such in silico analysis 17
would ideally yield a comp ehensi e, eely accessible da abase comp ising all calcula ed and 18
p edic ed sel -assembly p ope ies o he a ious gela o s, which would be a emendous esou ce 19
o he ield.54,130 20
Wi hou doub , he de elopmen o obus e alua ion s anda ds in he ield is o he u mos 21
impo ance o allow a compa ison o di e en hyd ogel composi ions, p in ing echniques, and 22
cell en apmen s a egies. This will aid in he de elopmen o new applica ion-speci ic 23
34
o mula ions and will conside ably ad ance he ield by allowing a be e unde s anding o he 1
unde lying mechanics o bioink p in abili y. 2
3
35
1
Figu e 1. P ope ies and applica ions o ideal sup amolecula hyd ogels in he ield o issue 2
enginee ing and biomedicine. Rep oduced wi h pe mission om e 36. Copy igh 2021 MDPI. 3
Rep oduced wi h pe mission om h p://sma .se ie .com/. Copy igh 2022 Se ie Medical A . 4
5
36
1
Figu e 2. (A) Nonco alen in e ac ions in ol ed in he o ma ion o sup amolecula hyd ogels. 2
(B) Classi ica ion o sup amolecula hyd ogels based on he ype o building block: (i) molecula 3
hyd ogel, (ii) sup amolecula polyme ic hyd ogel and (iii) sup amolecula hyb id hyd ogel. 4
5
37
1
Figu e 3. (A) (i) Molecula sca old o nucleosides and nucleo ides. Co alen ly, a achmen o a 2
nucleobase o a D- ibose ia a glycosidic bond o ms a nucleoside. When one o mo e phospha e 3
g oups a e p esen , i e e s o a nucleo ide. The phospha e (g een) g oup can be u ilized o 4
elec os a ic in e ac ions in he hyd ogel ne wo k. (ii) Molecula schema ics o DNA and RNA‘s 5
i e ni ogenous bases (nucleobases). (B) Hyd ogen dono (o ange a ow) and accep o (blue 6
a ow) g oups o guanosine p o ide dis inc pa hways o molecula ecogni ion o sel -assembly. 7
(C) Hoogs een and Wa son-C ick ace o guanosine. Guanine and guanine de i a i es may a ange 8
in o (D) guanosine qua e s (G-qua e ) and (E) guanosine ibbons (G- ibbons) in he p esence o 9
absence o me al ions, espec i ely. 10
11

38
1
Figu e 4. (A) P oposed sel -assembly mechanism o hymidine (Thd) and melamine (M) 2
hyd ogels a di e en molecula a ios o m ods, shee s, and lowe -like s uc u es (B) P oposed 3
sup amolecula o ganiza ion o helical ibe s in nucleolipid-based hyd ogels using hymidine-4
unc ionalized dipalmi oyl-sn-glyce ol phospha e (diC16dT). Wo m-like micelles a e o med in 5
he p esence o small coun e ions (Li+, Na+, K+) ia sel -assembly. TEM images o (i) non-6
unc ionalized 1,2-dipalmi oyl-sn-glyce ol-3-phospha e e sus (ii) hymidine- unc ionalized 7
DiC16dT (6% w/w, 0.9% NaCl). Inse shows a highe magni ica ion image. Panel A ep oduced 8
wi h pe mission om e 48. Copy igh 2011 Elsei e . Panel B ep oduced wi h pe mission om 9
e 49. Copy igh 2017 Wiley-VCH. 10
11
39
1
Figu e 5. (A) (i) P oposed molecula s uc u e o he cy idine bo a e dies e s ha sel -assemble 2
h ough elec os a ic in e ac ions ia sil e ions (Ag+) o o m sup amolecula hyd ogels. (ii) A 3
p oposed polyme iza ion mechanism o cy idine bo a e dies e s ha sel -assemble o o m 4
hyd ogels. (iii) Top: a omic o ce mic oscopy analysis o a hyd ogel made up o nanowi es (scale 5
ba 200 nm). Bo om: a b idge is o med by ex uding he hyd ogel (5.6 w % cy idine and dyed 6
wi h me hylene blue) wi h a sy inge unde shea s ess (scale ba 5 mm). (B) An imic obial 7
ac i i ies o sil e -s abilized cy idine bo a e hyd ogels agains a ious bac e ia. (i) Hyd ogel-8
dependen inhibi ion o E. coli, P. ae uginosa and S. au eus on LB aga pla es is shown. (ii) Dose-9
dependen educ ion o E. coli, P. ae uginosa and S. au eus colony- o ming uni s (CFUs). 10
Rep oduced wi h pe mission om e 51. Copy igh 2019 Ame ican Chemical Socie y. 11
40
1
Figu e 6. (A) S uc u al schema ic showing he chemical coo dina ion be ween AMP and Ag+. 2
(B) Pho og aphic compa ison wi h di e en concen a ions o AMP and Ag+. (i) Cons an AMP 3
concen a ion o 40 mmol L-1 wi h inc easing Ag+ concen a ions om le o igh (mmol L-1): 5, 4
10, 20, 30, 40, 50, 60; (ii) Cons an Ag+ concen a ion a 40 mmol L-1 wi h changing AMP 5
concen a ion (mmol L-1): 20, 30, 40, 50, 60, 70, 80; (iii) Cons an AMP and Ag+ concen a ion a 6
80 and 40 mmol L-1, espec i ely, wi h dec easing HNO3 concen a ion (mmol L-1): 50, 40, 30, 20, 7
10, 5, 0. (C) Enla ged ansmission elec on mic oscopy (TEM) image o sel -assembled hyd ogel 8
s uc u es o med in 40 mmol L-1 AMP/20 mmol L-1 Ag+. Rep oduced wi h pe mission om e 9
62. Copy igh 2017 Wiley-VCH. 10
41
1
Figu e 7. (A) Chemical s uc u es o guanposine and isoguanosine. (B) (i) 2D illus a ion 2
ep esen ing a so (guanosine: guanosine 5’-monophospha e (Guo:GMP) 1:6) and ha d 3
(Guo:GMP 1:1) hyd ogel. The di usion o he cy och ome C pa icles is ep esen ed wi h yellow 4
a ows. (ii) Me hylene blue (MB) elease p o ile om he hyd ogel a neu al pH. Di e en 5
Guo:GMP a io a e plo ed wi h blue (1:6), g een (1:2) and ed (1:1). (C) Chemical s uc u e o 6
Guo and isoguanosine (isoGuo) hyd ogels and scanning elec on mic oscopy (SEM) images o 7
Guo, isoGuo and Guo:isoGuo (1:1). Scale ba s o 3 μm. (D) (i) Schema ic illus a ion o 8
sup amolecula hyd ogel o med when sil e ions we e used o block he c ys alliza ion o he 2’-9
deoxy- luo oguanosine (FGd). (ii) Mic os uc u es o FGd hyd ogel a he concen a ion o 0.7% in 10
48
N4-oc anoyl-2′-
deoxycy idine (2’-dC-
N4-C8)
H-bonds, π-π s acking
C oss-linked ib ous ne wo k
Di usion-media ed elease o small molecula
weigh molecules
Injec able D ug deli e y
Tissue enginee ing 40
Adenosine-based sup amolecula hyd ogels
Adenine + benzene
ica boxylic acids
(1,3,5- is(4-
ca boxyphenyl)benzene
o biphenyl-3,49,5-
ica boxylic acid)
H-bonds, π-π s acking
Good mechanical s eng h
S imuli- esponsi e o empe a u e *
Biomedical enginee ing
D ug indus y
65,66
Adenine + ibo la in-5’ -
phospha e sodium sal
H-bonds, π-π s acking
Nano ib es p oduced due o o he chi al na u e o
he ibi yl g oup o ibo a in-5’-phospha e sodium
sal
S imuli esponsi e o pH, empe a u e, and shea
Hyd ogel o med a 30 °C
High s i ness
*
Cell imaging
Wound healing Tissue
enginee ing
67
5’-adenosine
monophospha e (5-
AMP) + β-i on
oxyhyd oxide (β-
FeOOH)
H-bonds, π-π s acking
Pa amagne ic hyd ogel
S imuli- esponsi e o pH, empe a u e, and
chemical en i onmen *
Magne ic esonance
imaging
D ug deli e y
Cell labelling
Magne ic sepa a ion
138
Guanosine-based sup amolecula hyd ogels
5-
GMP<sup>23,73</sup>
<sup>23,73</sup>
H-bonds, π-π s acking
Low li e ime s abili y
Remo e ca ionic and anionic dyes om aqueous
solu ion
* Tissue enginee ing 78,80
5-GMP + polyamines H-bonds, π-π s acking
Imp o ed gela ion e iciency *
An i umo al applica ions
Tissue enginee ing
87
5’-deoxy-5’-
iodoguanosine
+ KB(OH)4
H-bonds, π-π s acking, 5’-deoxy-
5’-iodoguanosine adop s a syn
con o ma ion, enabling
in amolecula cycliza ion
S imuli- esponsi e o empe a u e * D ug deli e y
Tissue enginee ing 29
Isoguanosine (isoGuo)
H-bonds, π-π s acking, mono alen
ion coo dina ion (Li+, Na+, K+,
Rb+, Cs+)
Addi ional dono and accep o g oups o he ou e
shell
Long- e m s abili y
Poo
injec abili y
D ug deli e y Nanoscopic
de ices cons uc ion
Tissue enginee ing
88
5-GMP H-bonds, π-π s acking,
coo dina ion o Fe
3+
and Ca
2+
)
pH- esponsi e elease o doxo ubicin * D ug deli e y
Tissue enginee ing
89

49
2’-deoxy-2’-
luo oguanosine H-bonds, π-π s acking
Addi ion o Ag+ blocks i s c ys alliza ion and
enhances i s s abili y (> 6 mon hs)
*
D ug deli e y
An ibac e ial applica ions
Tissue enginee ing
90
Guo + 5-GMP + KOH H-bonds, π-π s acking
5-GMP imp o es he solubili y o Guo
Insolubili y o Guo allows gela ion o 5-GMP a
lowe concen a ions
High nega i e cha ge in he hyd ogel
S imuli- esponsi e o pH
Di e en mola a io o Guo and GMP a ec s i s
mic oscopic and mac oscopic p ope ies
Injec able
Biomolecule
encapsula ion
Tissue enginee ing
82,93,9
4
Guo + isoGuo + KCl H-bonds, π-π s acking
Po ous lowe -like s uc u es
Enhanced s abili y
Injec able An icance he apy
Tissue enginee ing 56,95
5-GMP
H-bonds, π-π s acking,
coo dina ion o i alen ions
(La3+, Ce3+, Eu3+ and Tb3+), ion-
dipole in e ac ion be ween i alen
ions
and G
-
qua e s
S imuli- esponsi e o pH
Dense a angemen o nano ibe s induced by La3+
and Ce3
Highe mechanical s eng h
*
Elec on anspo Chi al
empla e
D ug deli e y
Tissue enginee ing
97
Guo + 8-
aminoguanosine
(8AmG)
H-bonds, π-π s acking,
coo dina ion o di alen ions (Ba2+,
S 2+ and Pb2+)
G ea e cha ge densi y
*
Tissue enginee ing
En i onmen al pu poses
applica ions
80
Guo + bo ic acid + KOH
H-bonds, π-π s acking, bo a e
dies e bond, coo dina ion o K+
S abili y o anionic dies e s gi en by p esence o
K+
Inc eased s abili y
Injec able D ug deli e y
Tissue enginee ing 39,55
Guo + 2- o mylbo onic
acid +
KOH
H-bonds, π-π s acking, bo a e
dies e bond, coo dina ion o K
+
Selec i i y o K
+
wi hou in e e ence om o he
alkali me al ions
Injec able Se um K+ de ec ion 100
Guo + 1-
naph halenebo onic acid
+ KOH
H-bonds, π-π s acking, bo a e
dies e bond, coo dina ion o K+
S imuli- esponsi e o pH, glucose and hyd ogen
pe oxide
Exhibi s be e biocompa ibili y o e di e en cell
lines
Injec able
P in able
D ug deli e y
Tissue enginee ing 101
Guo + 2- o mylbo onic
acid + is(2-
aminoe hyl)amine + KCl
H-bonds, π-π s acking,
iminobo ona e bond, coo dina ion
o K+
Iminobo ona e acili a ed hyd ogel o ma ion
S imuli- esponsi e o glucose and pH
*
Ze o-o de d ug elease
beha io
Tissue enginee ing
79
Guo + 2-FPBA + KOH
+ aminoglycoside
H-bonds, π-π s acking,
iminobo ona e bond, coo dina ion
o K+
Aminoglycosides wo k as good hyd ogel gela o s
Injec able
An imic obial applica ions
in i o
Tissue enginee ing
77
50
Guo + 2-FPBA + 4-A m
PEG-NH2
H-bonds, π-π s acking,
iminobo ona e bond, coo dina ion
o K+
S imuli- esponsi e o pH
Sel -healing p ope ies
Injec able
P in able
Cance he apy
Tissue enginee ing
102
Guo + benzene-1,4-
dibo onic acid + KOH
H-bonds, π-π s acking,
iminobo ona e bond, coo dina ion
o Mg2+
Inc eased s abili y * Tissue enginee ing 74
Guo + (B(OH)3) +
acyclo i +
me ho exa e + NaOH
H-bonds, π-π s acking, acyclo i is
inse ed in o he G-qua e
s uc u e and eplace Guo
molecules, lack o in e ac ion
be ween me ho exa e and he
hyd ogel
Wakened hyd ogel
S imuli- esponsi e o glucose, pH, ion
concen a ion
Lowe mechanical s eng h
Injec able
Encapsula ion o
molecules
Con olled d ug elease
Tissue enginee ing
22
Guo + bo ic acid + KOH
+ ecombinan human
collagen
H-bonds, π-π s acking
S ong hyd ophilici y
S imuli- esponsi e o pH, ligh , enzyme ac i i y,
ions and empe a u e
* In i o medical pa ches
Tissue enginee ing
75
Guo + phenylbo onic
acid +
ce yl ime hylammoniu
m b omide + NaOH
H-bonds, π-π s acking,
elec os a ic in e ac ions,
hyd ophobic in e ac ions
S uc u al modula ion by ce yl ime hylammonium
b omide concen a ion * Tissue enginee ing 103
Guo + a ylbo ona e
es e s (phenyl bo onic
acid, 4-ni ophenyl
bo onic acid) o
4me hoxyphenyl bo onic
acid) + KOH
H-bonds, π-π s acking,
coo dina ion o K+
S imuli- esponsi e o pH
Homogenous dis ibu ion o cells h oughou he
gel
Doesn’ equi e addi ional c osslinking s eps pos -
p in ing
3D p in ed
De elopmen o in i o
3D disease models o cell
sys ems
Tissue enginee ing
127
He e o ypic nucleoside-based sup amolecula hyd ogels
Bis-qua e na y
ammonium gemini
su ac an wi h 5’-
u idine monophospha e
(5-UMP) + adenosine
bases
H-bonds, π-π s acking
Adenine–u acil mix u e leads o agg ega ion bo h
in he bulk and a he ai – wa e in e ace
Injec able Biosenso s 105
Ac yla ed adenine +
ac yla ed hymine
hyd ogel + po assium
pe sul a e
H-bonds, π-π s acking Reusable adhesion beha iou and issue adhesi e
p ope ies in a ime-dependen manne Injec able
Wound d essing
Bio-glues
Tissue enginee ing
110
51
Adenine + u acil in o
PAAm chains + N,N’-
me hylene bis-
ac ylamide c osslinke +
po assium pe sul a e
H-bonds, π-π s acking
An i- a igue adhesi e and ough hyd ogel
High mechanical s eng h p o ided by co alen
bonds o MBA *
Wound d essing
Bio-glues
Cell and issue adhesi es,
Biomedical senso s and
elec odes
Tissue enginee ing
111
Guanine + Cyd
comp ising α-
cyclodex in, hioke als-
modi ied guanine and
cy osine- e mina ed PEG
H-bonds, π-π s acking
Rein o cemen e ec o H-bonds be ween Guo and
Cy
In oduc ion o hioke als endowed ROS-
esponsi i y
Injec able
D ug deli e y
An icance ea men
Tissue enginee ing
114
Guo and Cy + -3′- (1,2-
dipalmi oyl-sn-glyce o-
3-phospha e) and + NaCl
H-bonds, π-π s acking,
coo dina ion o Na+
Con olled elease o molecules by bo h nucleobase
and sal s Injec able
D ug deli e y
in i o injec ion and
implan a ion
Tissue enginee ing
115,116
*The co esponding publica ions did no gi e any in o ma ion on injec abili y o 3D p in abili y. Howe e , based on he p ope ies o
simila o mula ions, we expec hem o be injec able.
52
Co esponding Au ho
M. Godoy-Galla do, E-mail: [email protected], and R.A. Pe ez, E-mail: [email p o ec ed]
Au ho Con ibu ions
The manusc ip was w i en h ough con ibu ions o all au ho s. All au ho s ha e gi en app o al
o he inal e sion o he manusc ip .
ACKNOWLEDGMENT
M.G.-G. has ecei ed unding om he pos doc o al ellowship p og amme Bea iu de Pinós,
unded by he Sec e a y o Uni e si ies and Resea ch (Go e nmen o Ca alonia) and by he
Ho izon 2020 p og amme o esea ch and inno a ion o he Eu opean Union unde he Ma ie
Sklodowska-Cu ie g an ag eemen No 801370. M.A.M.-T. is suppo ed by he Spanish Minis y
o Science wi h he p ojec (RTI2018-096320-B-C21, 2018). R.A.P is suppo ed by he Spanish
Minis y by he Ramón y Cajal P og am (RYC2018-025977-I) and MINECO/FEDER p ojec
(RTI2018-096088-J-100). Addi ional inancial suppo was p o ided by he Go e nmen o
Ca alonia (2017 SGR 708).
M.G-G and M.M-G con ibu ed equally o his wo k.
ABBREVIATIONS
5-AMP, 5’-adenosine monophospha e; 8AmG, 8-aminoguanosine; FGd , 2’-deoxy-2’-
luo oguanosine; 5-IG, 5-deoxy-5-iodoguanosine; 2-FPBA, 2- o mylbo onic acid; 5-UMP, 5’-
u idine monophospha e; β-i on oxyhyd oxide (β-FeOOH); Ac , acyclo i ; Ade, adenine; Ado,
adenosine; NH4+, ammonium; AFM, a omic o ce mic oscopy; Ba2+, ba ium ion; Ca2+, BDBA,
benzene-1,4-dibo onic acid; BAs, bo ic acids; calcium ion; CRL, candida ugose lipase; CTAB,
53
ca ionic su ac an ce yl ime hylammonium b omide; CD, ci cula dich oism; Ce3+, ce ium ion;
CA-Fe3O4 NPs, ci ic acid-modi ied i on oxide nanopa icles; CDEX, cyclodex in; Cyd,
cy idine; 5-CMP, cy idine 5’-monophospha e; Cy , cy osine; M2+, di alen ca ions; E. coli,
Esche ichia coli; Eu3+, eu opium ion; ECM, ex acellula ma ix; FTIR, ou ie ans o m
in a ed; diC16-3′-G, G-3′-1,2-dipalmi oyl-sn-glyce o-3-phospha e; GSH, glu a hione; Gua,
guanine; Guo, guanosine; 5-GMP, guanosine 5’-monophospha e; GB, guanosine-bo a e; G4,
guanosine-quad uplex; G-qua e s, guanosine qua e s; G- ibbons, guanosine ibbons; Fe3+, i on
(III) ion; HGF, human gingi al ib oblas s; H-bonds, hyd ogen bonds; isoGuo, isoguanosine;
La3+, lan hanum ion; Li+, li hium ion; LMWG, low molecula weigh building blocks; Mg2+,
magnesium ion; MBA, N,N’-me hylene bis-ac ylamide; Hg2+, me cu y ion; MTX, me ho exa e;
MB, me hylene blue; NapBA, 1-naph halenebo onic acid; NHDF, no mal human de mal
ib oblas s; NLs, nucleo ide-based lipid; PBA, phenyl bo onic acid; PBS, phospha e bu e ed
saline; P 2+, pla inum ion; p-NPP, p-ni ophenylpalmi a e; PAAm, poly(ac ylamide); PLA,
polylac ic acid; KOH, po assium hyd oxide; K+, po assium ion; P. ae uginosa , Pseudomonas
ae uginosa; C-PEG-C, e minal Cy - unc ionalized PEG; PEG, hiola ed poly(e hylene glycol);
RHC, ecombinan human collagen; RP, ibo la in-5’-phospha e sodium sal ; SEM, scanning
elec on mic oscopy; Ag+, sil e ; Na+, sodium ion; SCAP, s em cells om he apical papilla;
S 2+, s on ium ion; S. au eus, S ep ococcus au eus; Tb3+, e bium ion; G-TK-G, hioke als-
modi ied guanine; TEM, ansmission elec on mic oscopy; ThT, hio la in-T; 3D, h ee
dimensional; Thd, hymidine; Thy, hymine; E 3NH+, ie hyl ammonium; TAEA, is(2-
aminoe hyl)amine; U a, u acil; Zn2+, zinc.
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