Innovations in Cancer Therapy: Endogenous Stimuli-Responsive Liposomes as Advanced Nanocarriers

Academic Edi o : Ma ia Camilla
Be gonzi
Recei ed: 21 Decembe 2024
Re ised: 3 Feb ua y 2025
Accep ed: 9 Feb ua y 2025
Published: 13 Feb ua y 2025
Ci a ion: To es, J.; Valenzuela Oses,
J.K.; Rabasco-Ál a ez, A.M.;
González-Rod íguez, M.L.; Ga cía,
M.C. Inno a ions in Cance The apy:
Endogenous S imuli-Responsi e
Liposomes as Ad anced Nanoca ie s.
Pha maceu ics 2025,17, 245.
h ps://doi.o g/10.3390/
pha maceu ics17020245
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Re iew
Inno a ions in Cance The apy: Endogenous S imuli-Responsi e
Liposomes as Ad anced Nanoca ie s
Jazmín To es 1,2,† , Johanna Ka ina Valenzuela Oses 1,2,†, An onio Ma ía Rabasco-Ál a ez 3,
Ma ía Luisa González-Rod íguez 3,* and Mónica C is ina Ga cía 1,2,*
1
Depa amen o de Ciencias Fa macéu icas, Facul ad de Ciencias Químicas, Uni e sidad Nacional de Có doba,
Haya de la To e and Medina Allende, Ciudad Uni e si a ia, Science Building 2, Có doba X5000HUA,
A gen ina; jaz. o [email p o ec ed] (J.T.); [email p o ec ed] (J.K.V.O.)
2Unidad de In es igación y Desa ollo en Tecnología Fa macéu ica, UNITEFA, Consejo Nacional de
In es igaciones Cien í icas y Técnicas, CONICET, Có doba X5000HUA, A gen ina
3Depa men o Pha macy and Pha maceu ical Technology, Facul y o Pha macy, Uni e sidad de Se illa,
C/P o . Ga cía González 2, 41012 Se ille, Spain; [email p o ec ed]
*Co espondence: [email p o ec ed] (M.L.G.-R.); mga [email p o ec ed] (M.C.G.)
†These au ho s con ibu ed equally o his wo k.
Abs ac : Recen ad ancemen s in nano echnology ha e e olu ionized cance
he apy—one
o he mos p essing global heal h challenges and a leading cause o dea h— h ough he
de elopmen o liposomes (L), lipid-based nano esicles known o hei biocompa ibili y
and abili y o encapsula e bo h hyd ophilic and lipophilic d ugs. Mo e ecen inno a ions
ha e led o he c ea ion o s imuli- esponsi e L ha elease hei payloads in esponse o
speci ic endogenous o exogenous igge s. Dual- and mul i- esponsi e L, which eac
o mul iple s imuli, o e e en g ea e p ecision, imp o ing he apeu ic ou comes while
educing sys emic oxici y. Addi ionally, hese sma L can adjus hei physicochemical
p ope ies and mo phology o enable si e-speci ic a ge ing and con olled d ug elease,
enhancing ea men e icacy while minimizing ad e se e ec s. This e iew explo es he
la es ad ancemen s in endogenous s imuli- esponsi e liposomal nanoca ie s, as well as
dual- and mul i- esponsi e L ha in eg a e in e nal and ex e nal igge s, wi h a ocus on
hei design s a egies, mechanisms, and applica ions in cance he apy.
Keywo ds: lipid esicles; s imuli-sensi i e nanoca ie s; cance nanomedicine;
d ug deli e y
1. In oduc ion
Cance ep esen s he second mos p ominen cause o dea h in he wo ld. Acco ding
o he la es global cance s a is ics om he GLOBLOCAN p ojec in 2020, he e we e
app oxima ely 19.3 million new cases and 10 million cance dea hs wo ldwide [
1
]. The
main cance ea men me hods include su ge y, adio he apy, chemo he apy, and im-
muno he apy. Howe e , hese me hods p esen ad e se side e ec s, such as a igue, hai
loss, in ec ions, pain, nausea, mucosi is, and omi ing, ha can signi ican ly educe he
quali y o li e o cance pa ien s [2].
In ecen yea s, a new s a egy in cance he apy, known as a ge ed d ug deli e y
sys ems, has been de eloped o imp o e cance he apies. These sys ems include micelles,
dend ime s, liposomes (L), solid nanopa icles, ca bon nano ubes, silica nanopa icles,
and quan um do s [
3
]. These nanoca ie s help o e come he limi a ions o con en ional
cance he apies, such as low speci ici y, apid d ug clea ance, biodeg ada ion, and poo
a ge ing abili y. As a esul , nanomedicines enable mo e p ecise deli e y o an icance
d ugs, ensu ing con olled and s abilized elease a he umo si e [
4
]. Among hem, L a e
Pha maceu ics 2025,17, 245 h ps://doi.o g/10.3390/pha maceu ics17020245
Pha maceu ics 2025,17, 245 2 o 36
he mos success ul nanoca ie s and ha e ound nume ous applica ions in a ge ed d ug
deli e y. L we e i s disco e ed in he 1960s by Alec Bangham and, since hen, hey ha e
become he mos widely used nanomedicine ca ie s in a ge ed d ug deli e y sys ems [
5
].
L a e lipidic ca ie s ha can sel -assemble in wa e , composed o one o mo e am-
phiphilic phospholipids [
6
]. The L consis o an aqueous co e su ounded by a phospholipid
bilaye , and hey can be used o deli e bo h hyd ophilic as well as lipophilic d ugs [
7
], as
shown in Figu e 1.
Pha maceu ics 2025, 17, x FOR PEER REVIEW 2 o 35
cance he apies, such as low speci ici y, apid d ug clea ance, biodeg ada ion, and poo
a ge ing abili y. As a esul , nanomedicines enable mo e p ecise deli e y o an icance
d ugs, ensu ing con olled and s abilized elease a he umo si e [4]. Among hem, L a e
he mos success ul nanoca ie s and ha e ound nume ous applica ions in a ge ed d ug
deli e y. L we e i s disco e ed in he 1960s by Alec Bangham and, since hen, hey ha e
become he mos widely used nanomedicine ca ie s in a ge ed d ug deli e y sys ems
[5].
L a e lipidic ca ie s ha can sel -assemble in wa e , composed o one o mo e am-
phiphilic phospholipids [6]. The L consis o an aqueous co e su ounded by a phospho-
lipid bilaye , and hey can be used o deli e bo h hyd ophilic as well as lipophilic d ugs
[7], as shown in Figu e 1.
Figu e 1. Schema ic s uc u e o a liposome. The hyd ophilic co e is enclosed by a hyd ophobic
bilaye made o phospholipids and choles e ol, enabling he deli e y o bo h hyd ophilic agen s
wi hin he co e and hyd ophobic agen s wi hin he bilaye .
The L can be ca ego ized depending on size, he numbe o bilaye s, and he compo-
si ion. Based on he numbe o bilaye s and hei hickness, L a e classi ied in o la ge
unilamella esicles, small unilamella esicles, mul ilamella esicles, and mul i esicula
esicles [8]. Ano he classi ica ion includes he cha ge p esen on he L su ace, so hey
can be classi ied in o ca ionic, anionic, o neu al ypes. Depending on size, wi hin he
same chemical composi ion, L can exhibi diffe en physiological beha io s and ac i i ies
[9].
L-based d ug deli e y sys ems a e widely used o he deli e y o small molecules
and nucleic acids [10]. L exhibi many ad an ages o e o he deli e y sys ems, he mos
ema kable being hei biocompa ibili y and sa e y due o hei simila i y o biomem-
b anes [11]. They also imp o e he solubili y o lipophilic and amphiphilic d ugs, pas-
si ely a ge immune sys em cells, offe sus ained elease o sys emic and local admin-
is a ion, and exhibi imp o ed issue pene a ion [12].
To maximize he he apeu ic efficacy o adi ional nanoca ie s, s imuli- esponsi e
nanosys ems ha e been used as an al e na i e o umo -speci ic d ug deli e y. These
nanoca ie s may elease he d ug h ough a ious mechanisms, depending on exogenous
o endogenous s imuli a he ac ion si e. Exogenous s imuli include magne ic ields, ligh ,
elec ic ields, and ul asound, among o he s. S imuli applied emo ely enable a con ol-
lable and non-in asi e d ug elease, o en syne gizing wi h endogenous mechanisms o
enhance deli e y p ecision. Inno a i e app oaches, such as ligh -based pho o he mal o
pho odynamic he apy, magne ic ields, and ul asound, ha e shown p omise in enabling
Figu e 1. Schema ic s uc u e o a liposome. The hyd ophilic co e is enclosed by a hyd ophobic
bilaye made o phospholipids and choles e ol, enabling he deli e y o bo h hyd ophilic agen s
wi hin he co e and hyd ophobic agen s wi hin he bilaye .
The L can be ca ego ized depending on size, he numbe o bilaye s, and he com-
posi ion. Based on he numbe o bilaye s and hei hickness, L a e classi ied in o la ge
unilamella esicles, small unilamella esicles, mul ilamella esicles, and mul i esicula
esicles [
8
]. Ano he classi ica ion includes he cha ge p esen on he L su ace, so hey can
be classi ied in o ca ionic, anionic, o neu al ypes. Depending on size, wi hin he same
chemical composi ion, L can exhibi di e en physiological beha io s and ac i i ies [9].
L-based d ug deli e y sys ems a e widely used o he deli e y o small molecules and
nucleic acids [
10
]. L exhibi many ad an ages o e o he deli e y sys ems, he mos ema k-
able being hei biocompa ibili y and sa e y due o hei simila i y o biomemb anes [
11
].
They also imp o e he solubili y o lipophilic and amphiphilic d ugs, passi ely a ge
immune sys em cells, o e sus ained elease o sys emic and local adminis a ion, and
exhibi imp o ed issue pene a ion [12].
To maximize he he apeu ic e icacy o adi ional nanoca ie s, s imuli- esponsi e
nanosys ems ha e been used as an al e na i e o umo -speci ic d ug deli e y. These
nanoca ie s may elease he d ug h ough a ious mechanisms, depending on exogenous
o endogenous s imuli a he ac ion si e. Exogenous s imuli include magne ic ields, ligh ,
elec ic ields, and ul asound, among o he s. S imuli applied emo ely enable a con ol-
lable and non-in asi e d ug elease, o en syne gizing wi h endogenous mechanisms o
enhance deli e y p ecision. Inno a i e app oaches, such as ligh -based pho o he mal o
pho odynamic he apy, magne ic ields, and ul asound, ha e shown p omise in enabling
si e-speci ic d ug elease while minimizing sys emic exposu e, highligh ing hei po en ial
as complemen a y s a egies [13].
In con as , endogenous s imuli a e inhe en ly linked o he disease s a e, igge ing
d ug elease a he a ge si e wi hou he need o ex e nal in e en ion. The p ima y
ad an age o in e nal s imuli is hei high speci ici y and esponsi eness o he umo mi-
c oen i onmen , allowing o p ecise, con olled, and localized d ug deli e y. This a ge ed
Pha maceu ics 2025,17, 245 3 o 36
app oach no only enhances he apeu ic e icacy bu also educes ad e se e ec s by mini-
mizing o - a ge d ug dis ibu ion [
14
]. These s imuli include changes in pH, adenosine
iphospha e (ATP) concen a ion, hyd ogen pe oxide (H
2
O
2
), edox po en ial, hypoxia,
enzymes, e c. [
15
]. These s imuli- esponsi e nanoca ie s may enhance he biodis ibu-
ion o an icance d ugs, inc easing hei bioa ailabili y and imp o ing hei an i umo al
e icacy [16].
This e iew discusses he ecen ad ancemen s in a ious ypes o endogenous s imuli-
esponsi e L, including pH- esponsi e, enzyme- esponsi e, edox- esponsi e, eac i e
oxygen species (ROS)- esponsi e, and hypoxia- esponsi e L. Dual- and mul i- esponsi e
sys ems a e highligh ed, as hey ep esen some o he mos ad anced app oaches, o en
in eg a ing mul iple endogenous igge s and, in ce ain cases, combining wi h exogenous
s imuli o achie e enhanced p ecision and e icacy in cance he apy. F om an in eg a ed
pe spec i e, his e iew no only add esses liposomal design s a egies bu also e alua es
hei p ac ical applica ions in speci ic cance ea men s. By combining design, mechanisms,
and applica ions, his comp ehensi e app oach o e s a ele an con ibu ion o he ield,
p o iding insigh s ha ha e no been ho oughly co e ed in p e ious epo s.
2. S imuli-Responsi e Nanoca ie s
Ad ancemen s in nano echnology and i s applica ion in he biomedical ield ha e
c ea ed an oppo uni y o imp o e he e icacy o he apeu ic agen s. Di e en ypes o
cance ha e been success ully ea ed using nanoca ie s [
17
]. An icance he apeu ic
agen s, such as doxo ubicin (Dox), cispla in (Cis), pacli axel (P x), 5- luo ou acil, mi ox-
an one, can ha idin, and i ino ecan (IR), a e among he d ugs ha ha e been widely
used in nanomedicine [
18
]. To achie e hei ou comes, nanoca ie s should deli e he
bioac i e compounds (e.g., he apeu ic o imaging agen s) o he umo issues o cance
cells, imp o ing he diagnosis and he apeu ic e icacy. F om he poin o iew o cance
he apy, side e ec s should no be p esen in he ideal nanomedicine. Howe e , nume ous
ba ie s a e encoun e ed du ing ci cula ion o wi hin umo s, such as p o ein co ona o ma-
ion, deg ada ion, bu s elease o leakage o ca go, and ecogni ion and clea ance by he
mononuclea phagocy e sys em (MPS) [15].
D ug deli e y s a egies in cance he apy using nanoca ie s ha e enabled he selec-
ion o speci ic nanosys ems capable o e icien ly anspo ing he apeu ic agen s o umo
issues [
19
]. Among hese, s eal h L, commonly PEGyla ed o inco po a ing zwi e ionic o
glycosyla ed lipids, ha e been used o enhance he ci cula ion ime and educe immune
clea ance, he eby imp o ing umo accumula ion. Simila ly, ackable L ha e eme ged as
a complemen a y ool, allowing eal- ime moni o ing o L dis ibu ion and d ug elease,
al hough hei applica ions a e p ima ily associa ed wi h ex e nal s imuli.
In ecen yea s, he use o s imuli- esponsi e nanoca ie s has u he imp o ed d ug
deli e y s a egies by enabling a ge ed elease o he apeu ic agen s in esponse o speci ic
endogenous o exogenous s imuli a he umo si e. In ecen yea s, imp o ed app oaches
o cance he apy ha e included he use o s imuli- esponsi e nanoca ie s, which can
achie e a ge ed elease o he apeu ic agen s when exposed o di e en endogenous o
exogenous s imuli a he umo si e.
Sys ems ha espond o endogenous s imuli ha e been widely used o sa e and
e icien d ug deli e y applica ions in cance nanomedicine. Based on he p omising
biomedical applica ions o hese nanoca ie s o cance he apy, his e iew highligh s
cu en and eme ging app oaches using hese s imuli s a egies in cance nanomedicine
o deli e ing bioac i e compounds. Special emphasis is placed on endogenous s imuli-
esponsi e L, including pH, enzymes, edox, ROS, and hypoxia (Figu e 2). This e iew also
discusses dual- and mul i-s imuli- esponsi e elease sys ems, which p o ide dis inc ad-
Pha maceu ics 2025,17, 245 4 o 36
an ages o d ug deli e y in cance nanomedicine, including s eal h L. Addi ionally, some
examples o ackable L a e discussed as a complemen a y ool o eal- ime moni o ing o
d ug dis ibu ion and elease.
Pha maceu ics 2025, 17, x FOR PEER REVIEW 4 o 35
Sys ems ha espond o endogenous s imuli ha e been widely used o sa e and e -
icien d ug deli e y applica ions in cance nanomedicine. Based on he p omising bio-
medical applica ions o hese nanoca ie s o cance he apy, his e iew highligh s cu -
en and eme ging app oaches using hese s imuli s a egies in cance nanomedicine o
deli e ing bioac i e compounds. Special emphasis is placed on endogenous s imuli- e-
sponsi e L, including pH, enzymes, edox, ROS, and hypoxia (Figu e 2). This e iew also
discusses dual- and mul i-s imuli- esponsi e elease sys ems, which p o ide dis inc ad-
an ages o d ug deli e y in cance nanomedicine, including s eal h L. Addi ionally,
some examples o ackable L a e discussed as a complemen a y ool o eal- ime moni-
o ing o d ug dis ibu ion and elease.
Figu e 2. Schema ic ep esen a ion o endogenous s imuli- esponsi e liposomes.
2.1. pH-Responsi e Liposomes
In he 1980s, esea che s de ined he concep o pH-sensi i e ca ie s [20]. Fo he i s
ime, esea ch ca ied ou showed ha he umo mic oen i onmen has a mo e acidic pH
compa ed o no mal issues. Fu he mo e, pH-sensi i e L can success ully deli e gene
agmen s and d ugs o he cy oplasm h ough he endocy ic pa hway [21]. Bo h a e key
ac o s in inc easing he d ug accumula ion on umo s and imp o ing hei in e naliza-
ion. Dox is widely used o he ea men o diffe en ypes o cance s, such as lung, colon,
b eas cance , and leukemia, bu i s use has been limi ed because i induces ca diomyopa-
hy [22]. pH-sensi i e L ha e been used as a s a egy o imp o e he he apeu ic speci ic-
i y, achie e con olled deli e y o d ugs, and educe d ug oxici y. L a e in e nalized and
aken up by endocy osis, whe e he ca go ends up ully o pa ially deg aded in he lyso-
some; hus, endea o s o a oid he p ocess o endocy osis we e made [23].
Se e al esea che s ha e de eloped pH-sensi i e liposomal o mula ions and s ud-
ied he mechanism by which L accumula e in he umo mic oen i onmen and hei ac-
i i y on umo cells. Table 1 p o ides a summa y o key s udies on pH-sensi i e L, acil-
i a ing a compa a i e o e iew. Addi ionally, some o he mos ecen and ele an s ud-
ies a e discussed in mo e de ail. Fo ins ance, Dos Reis e al. (2021) in es iga ed he ia-
bili y, in e naliza ion, in acellula afficking, and in acellula deli e y mechanism o
pH-sensi i e Dox-con aining L (SpHL-Dox) in human ce ical ca cinoma (HeLa) cells and
epo ed a g adual dec ease in he numbe o cells eaching 50% o ini ial alues a 24 h.
Also, in e naliza ion o SpHL-Dox in he p esence o pha macological inhibi o s showed
ha none o he inhibi o s educed he pe cen age o in e naliza ion a e 4 h o exposu e
[24]. Fu he mo e, s udies ca ied ou using acidi ica ion inhibi o s o e alua e he ole o
Figu e 2. Schema ic ep esen a ion o endogenous s imuli- esponsi e liposomes.
2.1. pH-Responsi e Liposomes
In he 1980s, esea che s de ined he concep o pH-sensi i e ca ie s [
20
]. Fo he i s
ime, esea ch ca ied ou showed ha he umo mic oen i onmen has a mo e acidic pH
compa ed o no mal issues. Fu he mo e, pH-sensi i e L can success ully deli e gene
agmen s and d ugs o he cy oplasm h ough he endocy ic pa hway [
21
]. Bo h a e key
ac o s in inc easing he d ug accumula ion on umo s and imp o ing hei in e naliza ion.
Dox is widely used o he ea men o di e en ypes o cance s, such as lung, colon, b eas
cance , and leukemia, bu i s use has been limi ed because i induces ca diomyopa hy [
22
].
pH-sensi i e L ha e been used as a s a egy o imp o e he he apeu ic speci ici y, achie e
con olled deli e y o d ugs, and educe d ug oxici y. L a e in e nalized and aken up by
endocy osis, whe e he ca go ends up ully o pa ially deg aded in he lysosome; hus,
endea o s o a oid he p ocess o endocy osis we e made [23].
Se e al esea che s ha e de eloped pH-sensi i e liposomal o mula ions and s udied
he mechanism by which L accumula e in he umo mic oen i onmen and hei ac i i y
on umo cells. Table 1p o ides a summa y o key s udies on pH-sensi i e L, acili a ing
a compa a i e o e iew. Addi ionally, some o he mos ecen and ele an s udies a e
discussed in mo e de ail. Fo ins ance, Dos Reis e al. (2021) in es iga ed he iabili y, in e -
naliza ion, in acellula a icking, and in acellula deli e y mechanism o pH-sensi i e
Dox-con aining L (SpHL-Dox) in human ce ical ca cinoma (HeLa) cells and epo ed a
g adual dec ease in he numbe o cells eaching 50% o ini ial alues a 24 h. Also, in e nal-
iza ion o SpHL-Dox in he p esence o pha macological inhibi o s showed ha none o he
inhibi o s educed he pe cen age o in e naliza ion a e 4 h o exposu e [
24
]. Fu he mo e,
s udies ca ied ou using acidi ica ion inhibi o s o e alua e he ole o in aluminal pH in
he elease o Dox om liposomal o mula ions epo ed an inc eased elease o Dox when
ca hepsins we e inhibi ed.
Pha maceu ics 2025,17, 245 5 o 36
Table 1. Examples o pH- esponsi e liposomes, including hei main cha ac e is ics and s age o
de elopmen .
Liposome
Composi ion
The apeu ic Agen s
Loaded
Biomedical
Applica ion
S age o
De elopmen Re .
HSPC, CHOL, and
GC Dox Fib osa coma
P eclinical (mu ine
xenog a umo
model)
[25]
MGlu, HA, and
CHex-HA Dox Ce ix cance
B eas cance
P eclinical (mu ine
colon model) [26]
CHOL, DSPE,
PEG2000, and SPC P x Melanoma
B eas cance
P eclinical
( umo -bea ing mice)
[27]
Pep ide KLA, DMA,
DSPE, and SPC P x Lung cance P eclinical (nude
mice) [28]
EYPC and
MGlu-HPG O albumin Lymphoma P eclinical (C57BL/6
mice) [29]
DMAP, SPC, PEG,
DSPE, and DCC Dox Melanoma In i o (A375 cance
cell line) [30]
EYPC, DOPE, MGlu,
MPLA, and DEX O albumin Lymphoma P eclinical (C57BL/6
mice) [31]
DPPC, CHOL, and
DC Dox Os eosa coma
In i o (K7M2 and
NIH/3T3 cance cell
lines)
[32]
PC, DOPE, DSPE,
PEG2000, and HA Dox B eas cance In i o (MCF-7
cance cell line) [33]
HSPC, DOPE, DSPE,
PEG2000, and CHOL Dox B eas cance P eclinical (BALB/c
mice) [34]
DSPE, PEG2000, and
CHOL Em ansine B eas cance P eclinical (mu ine
RAW 264.7) [35]
CHEMS, DOPE,
DSPE, PEG2000, and
CHOL
Gemci abine Panc ea ic cance P eclinical (MIA
PaCa-2 cells) [36]
EPC, CHEMS, DOPE,
DSPE, PEG2000, and
CHOL
Dox Glioma P eclinical (BALB/c
nude mice) [37]
CHEMS, DOPE, SPE,
and PEG2000 5-Fluo ou acil B eas cance
In i o
(MDA-MB-231 and
SK-BR-3 cance cell
lines)
[38]
CHOL, SPC, DSPE,
and PEG5000
Bo ine se um
albumin Bladde cance P eclinical (C57BL/6
mice) [39]
DOPE, CHOL, and
DC Resiquimod Colo ec al cance P eclinical (BALB/c
mice) [40]
CHEMS, DOPE,
DSPE, and PEG2000
Radio ace (99mTc-
HYNIC-βAla-
Bombesin(7–14))
B eas cance P eclinical (BALB/c
mice) [41]
CHEMS, DPPC,
DSPE, and PEG2000
Doce axel
Doxycycline hycla e Lung cance P eclinical (BALB/c
mice) [42]

Pha maceu ics 2025,17, 245 6 o 36
Table 1. Con .
Liposome
Composi ion
The apeu ic Agen s
Loaded
Biomedical
Applica ion
S age o
De elopmen Re .
HSPC, HA, and
DEAP Doce axel Colon ca cinoma P eclinical (BALB/c
mice) [43]
DOPE, DOTAP, and
PC Doce axel B eas cance P eclinical (Swiss
albino mice) [44]
DOPE, CHEMS,
DSPE, and PEG750 o
PEG2000
Calcein Glioblas oma
P eclinical (mu ine
model o
glioblas oma)
[45]
SPC and CHOL
Pacli axel
hyd oxyp opyl-β-
cyclodex in complex
Lung cance P eclinical (BALB/c
mice) [46]
DOPE, CHEMS,
DSPE, CHOL, HSPC,
and PEG2000
Dox Ce ical cance In i o
(HeLa cance
cell line) [24]
DOPE, CHEMS,
DSPE, and PEG2000 Dox B eas cance P eclinical (BALB/c
mice) [47]
DOPE, CHEMS,
CHOL, DSPE, and
PEG2000
Pep idomime ic-
doxo ubicin
conjuga e
Lung cance
B eas cance
P eclinical (BALB/c
nude mice) [48]
DOPE, CHOL, DSPE,
PEG2000, and CL Dauno ubicin Melanoma In i o (B16-BL6
cance cell line) [49]
DOPE, CHEMS,
DSPE, and PEG2000
Sim as a in
Dox B eas cance
In i o
(MDA-MB-231,
MCF-7, and SK-BR-3
cance cell lines)
[50]
DOPE, CHEMS,
DSPE, PEG2000, and
EDC
Doce axel B eas cance P eclinical (Dawley
a s) [51]
PC, CHOL, and
CHEMS Mo in
Hepa ocellula
cance
B eas cance
Lung cance
Gas ic cance
P eclinical (BALB/c
nude mice) [52]
DPPC, DSPE,
PEG2000, DOPE, and
CHOL
Echinomycin B eas cance
Lung cance
In i o
(MDA-MB-231,
MCF-7, and A549
cance cell lines)
[53]
DOPE, CHEMS, and
PEG2000
Cu(II) complex
(Cu(1,10-
phenan h oline)Cl2)
Colo ec al ca cinoma
P eclinical (BALB/c
mice) [54]
DOPE, CHEMS,
CHOL, DSPE, and
PEG2000
I ino ecan
Colo ec al ca cinoma
P eclinical (BALB/c
mice) [55]
Pha maceu ics 2025,17, 245 7 o 36
Table 1. Con .
Liposome
Composi ion
The apeu ic Agen s
Loaded
Biomedical
Applica ion
S age o
De elopmen Re .
DPPE and PEG2000 Imidazole
Ce ical cance
B eas cance
Lung cance
In i o
(MDA-MB-231,
MDA-MB-468, and
A549 cance cell
lines)
[56]
DOTAP, DOPE, and
CHOL
So a enib and
VEGF-siRN
Hepa ocellula
ca cinoma
P eclinical (Kunming
mice) [57]
Eud agi ®S100, OA,
CHOL, and SC Cu cumin Colon cance In i o (Caco-2
cance cell line) [58]
EPC and CHEMS Ca bopla in Lung cance In i o (A549 cance
cell line) [59]
Abb e ia ions: HSPC: hyd ogena ed soy phospha idylcholine; CHOL: choles e ol; GC: glycol chi osan;
MGlu: 3-me hylglu a yla ed; HA: hyalu onic acid; CHex-HA: 2-ca boxy cyclohexane-1-ca boxyla e; DSPE:
1,2-dis ea oyl-sn-glyce o-3-phosphoe hanolamine; PEG: poly(e hylene glycol); SPC: soybean phospholipids;
KLA: pep ide; DMA: dime hylmaleic anhyd ide; EYPC: egg yolk phospha idylcholine; MGlu-HPG:
3-me hylglu a yla ed hype b anched; DMAP: dime hylamino py idine; DCC: dicyclohexylca bodiimide; DOPE:
L-dioleoyl phospha idyle hanolamine; MPLA: monophospho yl lipid A; DEX: dex an; DPPC: 1,2-dipalmi oyl-
sn-glyce o-3-phosphocholine; DC: dime hylaminoe hane-ca bamoyl; EPC: egg phospha idylcholine; CHEMS:
choles e yl hemisuccina e; DEAP: 3-die hylaminop opyl; PC: phospha idylcholine; DOTAP: 1,2-dioleoyl-3-
ime hylammonium p opane; CL: ca diolipin; EDC: e hyl ca bodiimide hyd ochlo ide; DSPC: 1,2-dis ea oyl-sn-
glyce o-3-phosphocholine; DPPE: 1,2-dipalmi oyl-sn-glyce o-3-phosphoe hanolamine; OA: oleic acid; SC: sodium
chola e; ES100: Eud agi ®S 100.
To imp o e liposomal endocy osis, a ious ligands can be added o he su ace o
L based on o e exp essed ecep o s on he su ace o cance cells [
60
]. A p e ious s udy
epo ed ha ola e ecep o -be a (FR
β
) is highly exp essed in non-small-cell lung cance
on umo issues [
61
]. Fu he mo e, FR
β
is highly exp essed in an i-in lamma o y M2-
pola ized umo -associa ed mac ophages and has been success ully used as a molecula
a ge in he apeu ic s a egies o lung cance [
62
]. In his app oach, Pa k e al. (2021)
e ealed ha doce axel/doxycycline-loaded FR
β
- a ge ed pH-sensi i e L agains umo -
associa ed mac ophages and non-small-cell lung cance showed a syne gis ic inhibi o y
e ec on umo g ow h and supp essing he ac i i y o calpain-2 o e exp essed in non-
small-cell lung cance [42].
Simila s udies using ligands on he su ace o L we e epo ed by Oli ei a Sil a e al.
(2023). They e alua ed cy o oxici y, cellula up ake, and
in i o
acu e oxici y o a no el
Dox-loaded ola e-coa ed pH-sensi i e L (SpHL-Dox-Fol) in ola e ecep o (FR+) b eas
cance cells (MDA-MB-231 and MCF-7) and FR lung cance cells (A549). IC
50
alues o
518, 450, and 387 nM we e epo ed o Dox, SpHL-Dox, and SpHL-Dox-Fol, espec i ely.
In addi ion, SpHL and SpHL-Dox did no show cy o oxici y (~100% o cell iabili y).
Fu he mo e, cellula up ake was inc eased when Dox was encapsula ed in SpHL-Fol L
(30.1
±
2.7%). O gan oxici y was e alua ed in he li e , kidney, and hea . No o gan
damage was obse ed wi h SpHL-Dox-Fol. SpHL-Dox-Fol signi ican ly dec eased he
sys emic oxic e ec s o Dox [47].
The majo d awback o Dox in cance ea men is i s lack o umo speci ici y. Nowa-
days, esea che s a e ying o modi y he exis ing po en an icance d ugs o imp o e he
speci ici y o cance cells, solubili y, and e icacy. Speci ic agen s ha bind o o e exp essed
cell su ace ecep o s on he umo cells ha e been conside ed as a s a egy o imp o e Dox
selec i i y and an icance ac i i y.
Sonju e al. (2022) cons uc ed a pH-sensi i e liposomal o mula ion con aining a
pep idomime ic-Dox conjuga e (PS5-Dox-L) a ge ing human epide mal g ow h ac o
Pha maceu ics 2025,17, 245 8 o 36
ecep o -2 (HER2)-posi i e lung and b eas cance cells. These esea che s ound ha
elease o he d ug conjuga e and cellula up ake inc eased in lowe pH condi ions in HER2-
posi i e cance cells, as shown in Figu e 3[
48
]. As men ioned, L a e esicles composed
o a lipid bilaye and an aqueous inne , whe e hyd ophilic and hyd ophobic moie ies
a e en apped in he bilaye memb ane and aqueous phase, espec i ely [
63
]. L di e
om each o he due o hei lipid bilaye composi ion, which de e mines hei igidi y,
size, elease a e, and su ace cha ge. Fo ins ance, sa u a ed-phospholipid-based L, such
as dipalmi oyl phospha idylcholine, showed high memb ane igidi y compa ed wi h
unsa u a ed phospholipid-con aining lipid memb anes [64].
Pha maceu ics 2025, 17, x FOR PEER REVIEW 7 o 35
cance cells (MDA-MB-231 and MCF-7) and FR lung cance cells (A549). IC
50
alues o 518,
450, and 387 nM we e epo ed o Dox, SpHL-Dox, and SpHL-Dox-Fol, espec i ely. In
addi ion, SpHL and SpHL-Dox did no show cy o oxici y (~100% o cell iabili y). Fu -
he mo e, cellula up ake was inc eased when Dox was encapsula ed in SpHL-Fol L (30.1
± 2.7%). O gan oxici y was e alua ed in he li e , kidney, and hea . No o gan damage
was obse ed wi h SpHL-Dox-Fol. SpHL-Dox-Fol signi ican ly dec eased he sys emic
oxic effec s o Dox [47].
The majo d awback o Dox in cance ea men is i s lack o umo speci ici y. Now-
adays, esea che s a e ying o modi y he exis ing po en an icance d ugs o imp o e
he speci ici y o cance cells, solubili y, and efficacy. Speci ic agen s ha bind o o e ex-
p essed cell su ace ecep o s on he umo cells ha e been conside ed as a s a egy o
imp o e Dox selec i i y and an icance ac i i y.
Sonju e al. (2022) cons uc ed a pH-sensi i e liposomal o mula ion con aining a
pep idomime ic-Dox conjuga e (PS5-Dox-L) a ge ing human epide mal g ow h ac o e-
cep o -2 (HER2)-posi i e lung and b eas cance cells. These esea che s ound ha elease
o he d ug conjuga e and cellula up ake inc eased in lowe pH condi ions in HER2-pos-
i i e cance cells, as shown in Figu e 3 [48]. As men ioned, L a e esicles composed o a
lipid bilaye and an aqueous inne , whe e hyd ophilic and hyd ophobic moie ies a e en-
apped in he bilaye memb ane and aqueous phase, espec i ely [63]. L diffe om each
o he due o hei lipid bilaye composi ion, which de e mines hei igidi y, size, elease
a e, and su ace cha ge. Fo ins ance, sa u a ed-phospholipid-based L, such as dipal-
mi oyl phospha idylcholine, showed high memb ane igidi y compa ed wi h unsa u a ed
phospholipid-con aining lipid memb anes [64].
Figu e 3. The schema ic diag am o p epa a ion o he p oposed cance cell a ge ing mechanism
o a pH-sensi i e liposomal o mula ion con aining a pep idomime ic-doxo ubicin (Dox) conju-
ga e (PS5-DoxL). DOPE: 1,2-dioleoyl-sn-glyce o-3-phosphoe hanolamine; CHEMS: choles e yl
hemisuccina e; CHOL: choles e ol; DSPE-PEG: 1,2-Dis ea oyl-sn-glyce o-3-phosphoe hanolamine
(me hoxy(polye hylene glycol)-2000). Rep in ed wi h pe mission om Re . [48]
In ecen yea s, he use o L has conside ably inc eased, bu he e a e also some lim-
i a ions, including mainly hei sho se um hal -li e, which has been he bigges challenge
ha s ill needs o be su passed [65]. This limi a ion can be esol ed by conjuga ing hem
o polye hylene glycol (PEG) in pH-sensi i e L. By combining bo h s a egies, he hal -li e
o he pH-sensi i e L in he blood can be inc eased, along wi h he elease o he d ug a
he umo si e. Some esea che s, such as Al byawi e al. (2022), inco po a ed 1,2-dioleoyl-
sn-glyce o-3-phosphoe hanolamine (DOPE) in o pH-sensi i e L. DOPE caused he pH-
Figu e 3. The schema ic diag am o p epa a ion o he p oposed cance cell a ge ing mecha-
nism o a pH-sensi i e liposomal o mula ion con aining a pep idomime ic-doxo ubicin (Dox) con-
juga e (PS5-DoxL). DOPE: 1,2-dioleoyl-sn-glyce o-3-phosphoe hanolamine; CHEMS: choles e yl
hemisuccina e; CHOL: choles e ol; DSPE-PEG: 1,2-Dis ea oyl-sn-glyce o-3-phosphoe hanolamine
(me hoxy(polye hylene glycol)-2000). Rep in ed wi h pe mission om Re . [48].
In ecen yea s, he use o L has conside ably inc eased, bu he e a e also some
limi a ions, including mainly hei sho se um hal -li e, which has been he bigges chal-
lenge ha s ill needs o be su passed [
65
]. This limi a ion can be esol ed by conjuga ing
hem o polye hylene glycol (PEG) in pH-sensi i e L. By combining bo h s a egies, he
hal -li e o he pH-sensi i e L in he blood can be inc eased, along wi h he elease o he
d ug a he umo si e. Some esea che s, such as Al byawi e al. (2022), inco po a ed
1,2-dioleoyl-sn-glyce o-3-phosphoe hanolamine (DOPE) in o pH-sensi i e L. DOPE caused
he pH-sensi i e liposomal o mula ion o be s able a neu al pH and d ug elease unde
acidic condi ions due o he des uc ion o he liposomal bilaye [49].
The dauno ubicin-loaded pH-sensi i e liposomal sys em de eloped was es ed in
B16 and BL6 melanoma cell lines. Assays o d ug elease showed a apid elease o
dauno ubicin om pH-sensi i e L a pH 5.5 (50% o he d ug was eleased wi hin 8 h). The
pH-sensi i e L exhibi ed a highe cy o oxic and dauno ubicin cellula up ake e ec on B16
and BL6 cell lines. An al e na i e o imp o e e icacy in cance ea men was o associa e
Dox wi h o he an i umo d ugs; howe e , his s a egy has inc eased he side e ec s [
66
].
P e ious s udies poin ed ou ha sim as a in (Sim) inc eases he cy o oxic e ec o Dox
in b eas cance cell lines [
67
]. Da a epo ed by Dua e e al. (2021) demons a ed ha
Sim dec eased Dox-induced ca diac oxici y [
68
]. In his con ex , he associa ion o bo h
d ugs in he liposomal o mula ion could imp o e e icacy and educe oxici y. Recen ly,
Dua e e al. (2023) de eloped Sim/Dox-loaded pH-sensi i e L (Sp-HL-Dox-Sim) and
e alua ed he e ec o di e en a ios o encapsula ed d ugs agains human b eas umo
cell lines, such as MDA-MB 231, MCF-7, o SK-BR-3 cells. Sp-HL-Dox-Sim incuba ed a
Pha maceu ics 2025,17, 245 9 o 36
pH 5 showed Dox and Sim eleases o 90 and 65%, espec i ely. The inc eased size o
SpHL-Dox-Sim is also indica i e ha he liposomal o mula ion esponds o pH a ia ion.
Co-encapsula ion o Dox and Sim a 1:1 and 1:2 in pH-sensi i e L, espec i ely, signi ican ly
educed cy o oxic ac i i y. The IC
50
alue o Sp-HL-Dox-Sim 2:1 was 0.5 in all cell lines
in es iga ed. Fu he mo e, SpHL-Dox-Sim 2:1 showed a syne gis ic e ec in all ac ions
and agains all human b eas umo cell lines e alua ed [50].
In addi ion o hei use in d ug deli e y, pH-sensi i e L ha e eme ged as p omising
pla o ms o mRNA deli e y in cance immuno he apy. The success o mRNA-based
sys ems, such as SARS-CoV-2 accines, has d i en he explo a ion o lipid-based pla o ms
in oncology. In his con ex , expe imen al accines, like BNT122 (BioNTech) [
69
] and
mRNA-4157 (Mode naTX, Inc., Camb idge, MA, USA) [
70
], which use lipid nanopa icles
(LNPs), ha e been designed o induce immune esponses agains umo -speci ic an igens
in se e al ypes o cance . Al hough LNPs ha e shown e icacy in mRNA deli e y, pH-
sensi i e L also ep esen a e sa ile al e na i e, o e ing speci ic ad an ages in e ms o
s abili y, con olled elease, and compa ibili y wi h pe sonalized adminis a ion s a egies.
The abili y o pH-sensi i e L o acili a e cy oplasmic elease o mRNA in acidic en i-
onmen s makes hem key ools in he de elopmen o new cance he apies. Fo example,
Zhang e al. (2020) designed L modi ied wi h choles e ol-modi ied VQWRIRVAVIRK
pep ide (DP7-C) and 1,2-dioleoyl-3- ime hylammonium p opane (DOTAP) o enhance
mRNA ans ec ion in o dend i ic cells, p omo ing e icien endosomal escape and s ong
an i umo immune esponses in mu ine lung cance models [
71
]. Simila ly, Mai e al. (2020)
de eloped L-p o amine complexes o in anasal mRNA accine deli e y, a ge ing umo
an igens. These sys ems s abilized and p o ec ed mRNA encoding cy oke a in 19, enabling
e icien up ake by mucosal dend i ic cells and s ong ac i a ion o CD8+ T-cell esponses,
esul ing in signi ican umo g ow h educ ion and me as asis inhibi ion in p eclinical
lung cance models [72].
The con e gence o ad anced lipid-based echnologies unde sco es hei po en ial
as mul i unc ional pla o ms o cance ea men . Ini ially de eloped o an i i al ap-
plica ions, like COVID-19 accines, hese nanopla o ms ha e been adap ed o cance
immuno he apy, highligh ing he e sa ili y and ans o ma i e impac o pH-sensi i e
lipid sys ems in mode n biomedicine.
2.2. Enzyme-Responsi e Liposomes
Enzyme- esponsi e nanoca ie s a e nanos uc u es modi ied on hei su ace h ough
he bio-ca aly ic ac ion o enzymes. This ac i a ion imp o es he in e naliza ion o L,
leading o accele a ed d ug elease a he a ge si e [
73
]. Many enzyme-sensi i e nanos-
uc u es ha e been used o igge ing he deli e y o an icance d ugs, including enzyme-
esponsi e L.
Enzyme- esponsi e L a e associa ed wi h a selec i e enzyme loca ed in a a ge si e [
74
]
and hey exploi he con o ma ional change o he lipid bilaye associa ed wi h hese
enzymes ha , when emo ed, allow he d ug elease om L [75].
The enzymes used o enzyme-media ed d ug elease can be ei he ex acellula o
in e cellula . Among he many enzymes used o aid d ug deli e y o cance , p o eases,
phospholipases, and glycosidases may be included. Because p o eolysis is associa ed wi h
di e en diseases, se e al p od ugs, d ug deli e y sys ems, o bioma e ials ha e been
designed and de eloped o exe hei ac i i y in endosomal/lysosomal compa men s [
76
].
Fo ins ance, ca hepsin B is an impo an elemen o he lysosome cascade and is in ol ed
in umo in asion and me as asis [
77
]. One app oach ha could p o ide bene i s o
a ge ing lysosomes is he applica ion o ca ionic L. These induce lysosome memb ane
pe meabiliza ion and inhibi e lux. In his con ex , Lee e al. (2020) syn he ized a ca hepsin
Pha maceu ics 2025,17, 245 16 o 36
DHA-, BSO-, and CellROX-loaded liposomal nanopa icles (T -DBC NPs) o ea li e
cance , analyzing he gene a ion o ROS in HepG2 cells. Resul s e ealed an inc ease in
he gene a ion o ROS. Also, esea che s in es iga ed he essen ial ole o i on ion o he
gene a ion o ROS and showed ha Fe (II) induced ROS gene a ion when cance cells we e
ea ed wi h T -DBC NPs. In addi ion, assays demons a ed ha T -DBC NPs induced cell
apop osis due o he p esence o T [129].
Almos all p e ious s udies ca ied ou ha e ocused on he encapsula ion o syn he ic
d ugs. Nowadays, a ious ecen s udies ha e ocused on na u al esou ces o bioac i e
compounds and ied o ecognize hei po en ial agains cance cells [
130
]. Pipe longumine
(Pipe ) is a well-known alkaloid p esen in he Pipe longum plan ha possesses biological
ac i i y. Pipe induces apop osis by ROS accumula ion in cance cells ia di e en molecula
mechanisms. A ailable s udies sugges ed ha Pipe induces cy o oxici y in cance cells
mainly h ough he accumula ion o in acellula ROS [
131
]. In a ecen s udy, Pa een e al.
(2023) o mula ed Pipe -loaded L using he hin- ilm hyd a ion me hod and op imized hem
wi h Design-Expe
®
h ough esponse su ace me hodology o enhance d ug deli e y in
ce ical cance cells. Using Design-Expe
®
, hey op imized a iables, such as sonica ion
ime, phospha idylcholine- o-CHOL a io, and empe a u e, achie ing op imal pa icle size,
encapsula ion e iciency, and ze a po en ial. L demons a ed supe io e icacy in inducing
ROS p oduc ion, leading o a edox imbalance ha igge ed apop osis in squamous
ca cinoma (SiHa and HPV-16) and adenoca cinoma (HeLa and HPV-18) cell lines, wi h
apop osis a es o 63% and 73%, espec i ely, as shown in Figu e 5. Addi ionally, cell
mig a ion assays con i med ha L we e mo e e ec i e in inhibi ing cell mig a ion, a c i ical
ac o in cance p og ession [132].
Pha maceu ics 2025, 17, x FOR PEER REVIEW 16 o 35
Figu e 5. (a) G aphical 3D ep esen a ion o a esponse su ace plo and 2D con ou plo demon-
s a ing he effec o sonica ion ime (X1; min), a io o L-α-phospha idylcholine (SPC):choles e ol
(X2; %), and empe a u e (X3; °C) on pa icle size (Y1; nm), en apmen efficiency (EE; Y2; %), and
ze a po en ial (Y3; mV). (b) Pe cen o cell iabili y a e ea men wi h diffe en concen a ions o
Pipe longumine (Pipe ) and Pipe -loaded liposomes (Pipe -L): (1) SiHa cells and (2) HeLa cells. Da a
o h ee independen expe imen s, shown as mean ± SE (s a is ical signi icance: * p < 0.05, ** p < 0.01,
*** p < 0.001, and **** p < 0.0001). Copy igh 2023 Else ie . Rep in ed wi h pe mission om Re . [132].
2.5. Hypoxia-Responsi e Liposomes
Hypoxia is a pa hological cha ac e is ic ha is obse ed in 50–60% o solid umo s,
in which he umo cells a e dep i ed o an adequa e oxygen supply [133]. The su i al
o umo cells is inc eased by hypoxia h ough p ocesses such as angiogenesis, in asi e-
ness, and me as asis, and he dec eased he apeu ic effec and poo p ognosis o chemo-
he apy [134]. Despi e his, hypoxic cells can be exploi ed o he apy by non- oxic, hy-
poxia-ac i a ed p od ugs. Hypoxia-ac i able p od ugs a e ac i a ed by he in si u educ-
ion p ocess in hypoxic umo cells o induce oxici y and ha e been epo ed o cance
ea men s [135]. Howe e , he he apeu ic efficacy o small-molecule d ugs is limi ed in
clinical applica ions. Recen ly, d ug deli e y sys ems based on hypoxia- esponsi e nano-
pa icles in esponse o hypoxic umo mic oen i onmen s o umo - a ge ed d ug de-
li e y and he apy we e de eloped o sol e hese p oblems [136]. Fo example, Shah e al.
(2022) in es iga ed he ac i i y o inblas ine-N-oxide hypoxia-ac i a ed p od ug-loaded
L (CPD100-L) in panc ea ic duc al adenoca cinoma. CPD100-L was es ed o hei cell
p oli e a i e ac i i y unde hypoxic condi ions (0.1%) in Panc-1 and MiaPaCa-2 panc ea ic
cells. IC
50
alues o 62 ± 7 nM and 3 ± 0.4 nM a 0.1% oxygen in Panc-1 and MiaPaCa-2,
espec i ely, we e shown. They also obse ed ha no effec o emp y L on bo h cell lines
exis ed. To in es iga e he pene a ion and apop o ic effec o CPD100-L, 3D sphe oids o
Panc-1 we e used, and esul s e ealed sh inkage and dis up ion o he sphe oids, causing
cell dea h [137]. Some d ugs, such as pla inum (P ), a e widely applied in chemo he apy
ea men . All P d ugs impai no mal DNA unc ions by gene a ing monoadduc s as well
as DNA c osslinks [138]. Conside ing ha inhibi ion o DNA epai by a ge ed d ugs is
Figu e 5. (a) G aphical 3D ep esen a ion o a esponse su ace plo and 2D con ou plo demon-
s a ing he e ec o sonica ion ime (X1; min), a io o L-
α
-phospha idylcholine (SPC):choles e ol
(X2; %), and empe a u e (X3;
◦
C) on pa icle size (Y1; nm), en apmen e iciency (EE; Y2; %), and
ze a po en ial (Y3; mV). (b) Pe cen o cell iabili y a e ea men wi h di e en concen a ions o
Pipe longumine (Pipe ) and Pipe -loaded liposomes (Pipe -L): (1) SiHa cells and (2) HeLa cells. Da a
o h ee independen expe imen s, shown as mean
±
SE (s a is ical signi icance: * p< 0.05, ** p< 0.01,
*** p< 0.001, and **** p< 0.0001). Copy igh 2023 Else ie . Rep in ed wi h pe mission om Re . [
132
].

Pha maceu ics 2025,17, 245 17 o 36
2.5. Hypoxia-Responsi e Liposomes
Hypoxia is a pa hological cha ac e is ic ha is obse ed in 50–60% o solid umo s, in
which he umo cells a e dep i ed o an adequa e oxygen supply [
133
]. The su i al o u-
mo cells is inc eased by hypoxia h ough p ocesses such as angiogenesis, in asi eness, and
me as asis, and he dec eased he apeu ic e ec and poo p ognosis o chemo he apy [
134
].
Despi e his, hypoxic cells can be exploi ed o he apy by non- oxic, hypoxia-ac i a ed p o-
d ugs. Hypoxia-ac i able p od ugs a e ac i a ed by he in si u educ ion p ocess in hypoxic
umo cells o induce oxici y and ha e been epo ed o cance ea men s [
135
]. Howe e ,
he he apeu ic e icacy o small-molecule d ugs is limi ed in clinical applica ions. Recen ly,
d ug deli e y sys ems based on hypoxia- esponsi e nanopa icles in esponse o hypoxic
umo mic oen i onmen s o umo - a ge ed d ug deli e y and he apy we e de eloped
o sol e hese p oblems [
136
]. Fo example, Shah e al. (2022) in es iga ed he ac i i y o
inblas ine-N-oxide hypoxia-ac i a ed p od ug-loaded L (CPD100-L) in panc ea ic duc al
adenoca cinoma. CPD100-L was es ed o hei cell p oli e a i e ac i i y unde hypoxic
condi ions (0.1%) in Panc-1 and MiaPaCa-2 panc ea ic cells. IC
50
alues o 62
±
7 nM and
3±0.4 nM
a 0.1% oxygen in Panc-1 and MiaPaCa-2, espec i ely, we e shown. They also
obse ed ha no e ec o emp y L on bo h cell lines exis ed. To in es iga e he pene a ion
and apop o ic e ec o CPD100-L, 3D sphe oids o Panc-1 we e used, and esul s e ealed
sh inkage and dis up ion o he sphe oids, causing cell dea h [
137
]. Some d ugs, such as
pla inum (P ), a e widely applied in chemo he apy ea men . All P d ugs impai no mal
DNA unc ions by gene a ing monoadduc s as well as DNA c osslinks [
138
]. Conside ing
ha inhibi ion o DNA epai by a ge ed d ugs is a pi o al app oach o po en ia ing he
he apeu ic e icacy o Cis, some esea che s, such as Chen e al. (2021), o mula ed a
nanosys em based on glucose oxidase (GOx)/ i apazamine(Tpz)@L-P om a pla inum
(IV) p od ug as a building block, encapsula ed payloads o GOBx and he hypoxia ac i a -
able dual- unc ion chemo-d ug Tpz, and e alua ed hei e iciency in Cis- esis an umo s.
In i o
inhibi ion demons a ed ha GOx/Tpz@L-P had a highe oxygen consump ion
a e wi hin (BEL7404DDP) human hepa ocellula ca cinoma cells. In addi ion, he apeu ic
e ec s o GOx/Tpz@L-P in pa ien -de i ed umo o ganoids showed ha L inhibi ed he
p oli e a ion o umo o ganoids, indica ing po en e icacy. Fu he mo e, he in i o an i-
cance e icacy o GOx/Tpz@L-P in cell-line-de i ed xenog a models e idenced a po en
inhibi ion o umo g ow h. Also, esul s con i med ha GOx-ca alyzed oxygen ampli ied
he in a umo hypoxia. GOx/Tpz@L-P led o a comple e inhibi ion o he umo s in mice
(82.08%). Fu he mo e, he liposomal o mula ion showed ma kedly educed si es o li e
me as asis (~2 si es pe mouse) [139].
Al hough hese p od ugs ha e g ea e an icance e icacy, poo selec i i y and apid
elimina ion a e he bigges challenges hey a e con on ed wi h. Gi en hese poin s, ecen
e o s ha e ocused on new compounds, such as ni oa oma ics and azo de i a i es, due
o hei sensi i i y. Ni o educ ase has been widely used in he educ ion o ni oa oma ic
compounds in hypoxic condi ions and could be used o ac i a e p od ugs o chemo he a-
peu ic cance ea men [
140
]. He ein, Li e al. (2019) s udied Dox-loaded ni oimidazole-
de i a i e-inco po a ed L (Dox-L) o hypoxia- igge ed d ug deli e y. Unde hypoxic
condi ions, ni oimidazole de i a i e b eaks down he phospholipid bilaye , eleasing he
encapsula ed d ug, so Dox-L eleased o e 83% o he d ug a e 12 h. Cy o oxici y-assessed
human pha yngeal squamous ca cinoma (FaDu) and mouse p os a e cance (RM-1) cells
unde hypoxic condi ions (1% O
2
) showed a high cy o oxici y. Fu he mo e, he an i umo
e icacy was e alua ed using a cell-line-de i ed xenog a model by subcu aneously injec -
ing RM-1 cells in o he lank o C57BL/6 mice. Resul s showed ha Dox-L p olonged he
su i al ime in compa ison wi h Dox-L wi hou ni oimidazole de i a e (34 s. 25 days).
In addi ion, esea che s in es iga ed he ad e se e ec s o Dox-L on he body weigh s o
Pha maceu ics 2025,17, 245 18 o 36
he mice eco ded du ing he ea men . Da a e ealed ha Dox-L wi hou ni oimida-
zole de i a e showed less weigh gain s. Dox-L, indica ing be e umo inhibi ion [
141
].
Recen ly, esea che s ha e ecognized ha compa ed wi h ni oa oma ics, azo has been
he mos p omising hypoxia- esponsi e moie y o d ug ca ie s. Fo example, Long e al.
(2020) de eloped azo-based hypoxia- esponsi e hyb id L o Dox (Dox-HL) deli e y, a -
ge ing umo hypoxia. Dox-HL we e s udied unde no moxic and hypoxic condi ions.
Resul s showed ha Dox elease in no moxic condi ions was lowe han unde hypoxic
condi ions (20 s. 80%). Also, hypoxia- igge ed in a umo al d ug elease was assessed
in umo -bea ing C57BL/6 and BALB/c nude mice, and he esul s demons a ed high
hypoxia- igge ed in a umo al d ug elease in he hypoxic umo egions. In addi ion,
in i o
an i umo e icacy was assessed and, as expec ed, Dox-HL had a high inhibi ion o
umo g ow h. The su i al o mice was in good ag eemen wi h umo g ow h inhibi ion,
eaching 36 days [142].
As demons a ed abo e, azo-de i a i e molecules espond o he hypoxic egions and
ha e been used as hypoxia- esponsi e nanoca ie s in cance . Addi ionally, azobenzene
de i a i es ha e a educ ion po en ial ha alls wi hin he ange o hypoxic en i on-
men s [
143
]. Complex s a egies and expensi e ma e ials o de elop hypoxia-sensi i e
nanolipid o mula ions we e used. Nano-d ug deli e y sys ems, such as ca ionic L, gained
in e es due o he endency o each he umo mic oen i onmen . Howe e , ca ionic L
a e apidly clea ed by he MPS due o p o ein opsoniza ion [
144
]. PEGyla ion can a oid
nega i e e ec s in he clea ance, c ea ing a shielding laye a he su ace o ca ionic L and,
hence, he blood ci cula ion [
145
]. So, Mash eghi e al. (2022) designed and syn hesized a
ca ionic liposomal Dox deco a ed wi h an azo-based linke (PEG-Azo-L) o enhance an i u-
mo ac i i y unde hypoxic condi ions. This ac i i y was ca ied ou using C26 umo cells.
In he hypoxic mic oen i onmen , he azolinke clea age was ca alyzed by azobenzene
educ ase in hypoxia a eas and exposed he posi i e cha ges o ca ionic L, indica ing he
e icacy o he PEG-Azo-L o mula ion [
146
]. In ecen yea s, immuno he apy has been
a majo ocus among umo ea men s, especially wi h me as a ic cance s, whe e some
pa ien s, p e iously conside ed o be incu able, can su i e [
147
]. The use o an i-PD-1
o an i-PD-L1 monoclonal an ibodies exhibi ed sa is ac o y clinical esponses in se e al
cance s [148].
Recen ly, di e en s udies con i med he immunological e ec s o chemo he apy in
combina ion wi h immune checkpoin inhibi o he apy [
149
]. In non-small-cell lung cance ,
p omising esul s we e shown by combining chemo he apy o P wi h an i-PD-1/PD-L1
an ibodies. P may up egula e PD-L1 exp ession in umo issue and exe a nega i e
immunomodula o y e ec , which can be coun e ac ed by PD-1/PD-L1 inhibi o s h ough
hei ac ion pa hway [
150
]. Also, some esea che s ecen ly con i med ha inc eased u-
mo oxygena ion ia di e en designed s a egies could ema kably po en ia e cance
ea men s [
151
]. On app oach, Song e al. (2022) s udied me o min (me )-oxalipla in
(oxa)-loaded L (me -oxa-L) o po en ia e cance immuno he apy. Me -oxa-L was placed
on CT26 umo s o e alua e he in a umo al hypoxia s a us. I was de e mined ha he
pe cen age o hypoxia-posi i e a eas in umo slices o mice was 3.84%. Fu he mo e, by
moni o ing he umo supp ession e icacy, me -oxa-L showed he highes umo inhibi ion
e icacy. In addi ion, hese L we e able o p ime po en an i umo immune esponses by
inducing immunogenic cell dea h o cance cells and p omo ing umo oxygena ion [
152
].
Chemo he apy can enhance an i umo esponses h ough di e en mechanisms; howe e ,
some chemo he apy d ugs would lead o up egula ion o PD-L1 exp ession. Di e en om
con en ional chemo he apeu ics causing PD-L1 en ichmen , cyclopep ide RA-V (deoxy-
bou a din) ca ches ou a en ion because o i s sa is ac o y ac i i ies in cance cells [
153
]. In
iew o his, Yao e al. (2022) designed a syne gis ic an i umo pla o m, BMS/RA@CC-L,
Pha maceu ics 2025,17, 245 19 o 36
using CT26 cance -cell biomime ic nanopa icles, combining a chemo he apeu ic d ug (RA-
V) and PD-1/PD-L1 agains hypoxic umo . These esea che s incuba ed BMS/RA@CC-L
wi h monocy e/mac ophage-like cells o e alua e he an iphagocy osis capabili y, and his
liposomal o mula ion exhibi ed ema kably dec eased cellula up ake o BMS/RA@CC-L.
Fu he mo e, o analyze he
in i o
umo - a ge ing abili y, CT26 cell-memb ane-coa ed L
we e injec ed in o CT26 umo -bea ing nude mice. The mice ea ed exhibi ed a signi ican
luo escence enhancemen in he umo si e compa ed o no mal issues (4 h s. 24 h),
indica ing he high umo speci ici y o BMS/RA@CC-L [154].
3. Dual/Mul i-Responsi e Liposomes
S imuli- esponsi e L ha e eme ged as a p omising s a egy in cance he apy, le e ag-
ing he unique physiological and biochemical condi ions o he umo mic oen i onmen o
enable p ecise, con olled d ug elease. These nanoca ie s a e speci ically designed o e-
spond o endogenous signals, which a e o en dys egula ed in umo issues. Addi ionally,
hey can be ac i a ed by exogenous s imuli, p o iding esea che s wi h di e se mecha-
nisms o igge d ug elease [
155
,
156
]. This dual abili y o ha ness bo h endogenous and
exogenous clues makes s imuli- esponsi e L highly adap able in o e coming challenges,
such as inadequa e d ug a ge ing, accele a ed clea ance, and o - a ge oxici y.
In ecen yea s, he in eg a ion o mul iple s imuli wi hin a single deli e y sys em
gained signi ican a en ion due o i s po en ial o enhance he apeu ic p ecision and e icacy.
By combining wo o mo e s imuli, hese sys ems o e mo e e ined con ol o e d ug
elease, ensu ing ha he apeu ic agen s a e ac i a ed speci ically a he si e o ac ion.
This no only maximizes he d ug e ec i eness bu also educes sys emic side e ec s, a
c i ical conce n in con en ional chemo he apy [
4
]. Figu e 6p o ides an o e iew o he
a ious endogenous and exogenous s imuli combined in ecen s udies, illus a ing he
e sa ili y o hese dual/mul i-s imuli- esponsi e sys ems. The abili y o op imize d ug
deli e y h ough dual/mul i-s imuli- esponsi e L ep esen s a majo ad ancemen owa d
pe sonalized cance ea men s, whe e he apy can be cus omized o ma ch indi idual
umo cha ac e is ics and disease p og ession.
Among hese sys ems, dual-s imuli- esponsi e L, which espond o bo h empe a u e
and enzyma ic ac i i y, exempli y how such pla o ms can imp o e he apeu ic ou comes.
Lyu e al. (2018) de eloped a no el hyd ogel sys em whe e L se e as nonco alen c osslink-
e s and ca ie s o con olled elease o molecula payloads. This sys em is o med by
CHOL-modi ied DNA copolyme s and L, c ea ing a ma ix ha esponds o empe a u e
and enzyma ic ac i i y. Upon exposu e o hea o he enzyme EcoR I, a gel- o-sol ans o -
ma ion occu s, eleasing L loaded wi h hyd ophobic (DiIC18(5)) and hyd ophilic (calcein)
compounds.
In i o
s udies con i med he nanopla o m’s biocompa ibili y, along wi h i s
injec able and sel -healing p ope ies, posi ioning i as a po en ial candida e o biomed-
ical applica ions [
157
]. Simila ly, Palmese e al. (2020) designed empe a u e-sensi i e L
c osslinked wi hin a PEG hyd ogel o dual-s imuli- esponsi e d ug deli e y. These L,
composed o 1,2-dipalmi oyl-sn-glyce o-3-phosphocholine (DPPC) and 1,2-dis ea oyl-sn-
glyce o-3-phosphoe hanolamine-N-[maleimide (polye hylene glycol)-2000 (Mal), exhibi ed
a phase ansi ion a 41
◦
C, allowing empe a u e-induced d ug elease. C osslinked in o
a MMP-sensi i e PEG-pep ide hyd ogel, he L eleased Dox in esponse o bo h hype -
he mia (42
◦
C) and enzyma ic ac i i y. The sys em demons a ed sus ained d ug elease,
achie ing up o 80% unde hype he mia condi ions while exhibi ing minimal cy o oxici y
in ib oblas cul u es [158].
Pha maceu ics 2025,17, 245 20 o 36
Pha maceu ics 2025, 17, x FOR PEER REVIEW 19 o 35
ac ion. This no only maximizes he d ug effec i eness bu also educes sys emic side e -
ec s, a c i ical conce n in con en ional chemo he apy [4]. Figu e 6 p o ides an o e iew
o he a ious endogenous and exogenous s imuli combined in ecen s udies, illus a ing
he e sa ili y o hese dual/mul i-s imuli- esponsi e sys ems. The abili y o op imize
d ug deli e y h ough dual/mul i-s imuli- esponsi e L ep esen s a majo ad ancemen
owa d pe sonalized cance ea men s, whe e he apy can be cus omized o ma ch indi-
idual umo cha ac e is ics and disease p og ession.
Figu e 6. Diag am o dual/mul i-s imuli- esponsi e liposomes (L): The g ay lines ep esen speci ic
combina ions o s imuli ha ac i a e he d ug elease sys em, e lec ing in e ac ions desc ibed in he
e iew ex . This design illus a es how he L can simul aneously espond o endogenous (in yellow)
and exogenous (in g een) s imuli, op imizing he apeu ic efficacy.
Among hese sys ems, dual-s imuli- esponsi e L, which espond o bo h empe a-
u e and enzyma ic ac i i y, exempli y how such pla o ms can imp o e he apeu ic ou -
comes. Lyu e al. (2018) de eloped a no el hyd ogel sys em whe e L se e as nonco alen
c osslinke s and ca ie s o con olled elease o molecula payloads. This sys em is
o med by CHOL-modi ied DNA copolyme s and L, c ea ing a ma ix ha esponds o
empe a u e and enzyma ic ac i i y. Upon exposu e o hea o he enzyme EcoR I, a gel-
o-sol ans o ma ion occu s, eleasing L loaded wi h hyd ophobic (DiIC18(5)) and hyd o-
philic (calcein) compounds. In i o s udies con i med he nanopla o m’s biocompa ibil-
i y, along wi h i s injec able and sel -healing p ope ies, posi ioning i as a po en ial can-
dida e o biomedical applica ions [157]. Simila ly, Palmese e al. (2020) designed empe -
a u e-sensi i e L c osslinked wi hin a PEG hyd ogel o dual-s imuli- esponsi e d ug de-
li e y. These L, composed o 1,2-dipalmi oyl-sn-glyce o-3-phosphocholine (DPPC) and
1,2-dis ea oyl-sn-glyce o-3-phosphoe hanolamine-N-[maleimide (polye hylene glycol)-
2000 (Mal), exhibi ed a phase ansi ion a 41 °C, allowing empe a u e-induced d ug e-
lease. C osslinked in o a MMP-sensi i e PEG-pep ide hyd ogel, he L eleased Dox in e-
sponse o bo h hype he mia (42 °C) and enzyma ic ac i i y. The sys em demons a ed
sus ained d ug elease, achie ing up o 80% unde hype he mia condi ions while exhib-
i ing minimal cy o oxici y in ib oblas cul u es [158].
Based on he p inciple o combining mul iple physiological s imuli, in eg a ing pH
sensi i i y wi h empe a u e esponsi eness p o ides addi ional ad an ages o d ug
Figu e 6. Diag am o dual/mul i-s imuli- esponsi e liposomes (L): The g ay lines ep esen speci ic
combina ions o s imuli ha ac i a e he d ug elease sys em, e lec ing in e ac ions desc ibed in he
e iew ex . This design illus a es how he L can simul aneously espond o endogenous (in yellow)
and exogenous (in g een) s imuli, op imizing he apeu ic e icacy.
Based on he p inciple o combining mul iple physiological s imuli, in eg a ing pH
sensi i i y wi h empe a u e esponsi eness p o ides addi ional ad an ages o d ug
deli e y. In umo en i onmen s, whe e acidic pH is common, pH-sensi i e L o e a
complemen a y mechanism o u he enhance d ug elease. The combined e ec o hea
and pH may p omo e L des abiliza ion unde acidic condi ions and accele a e d ug elease
a ele a ed empe a u es. This dual app oach has demons a ed p omising esul s in
op imizing he apeu ic ou comes. Fo example, Zhou e al. (2019) de eloped P -ac idine
hyb id agen s encapsula ed in phospha idylcholine (PC) and CHOL-based L. Unde acidic
condi ions, hese L eleased 91.5% o hei d ug load wi hin 24 h, compa ed o jus 35.6%
unde neu al condi ions.
In i o
s udies demons a ed he highe cy o oxici y o he
hyb id agen o e Cis agains lung cance cells (NCI-H460), sugges ing a p omising s a egy
o o e come Cis esis ance in non-small-cell lung cance [159].
Following his app oach, Sen oukas e al. (2021) enginee ed chime ic L, inco po a ing
unc ional copolyme s o deli e cu cumin. Wi h he use o dual s imuli, he sys em
achie ed con olled elease while main aining s abili y ac oss di e en condi ions. The
encapsula ion e iciency and long- e m elease o cu cumin highligh ed he po en ial o
educe o - a ge e ec s and enhance he ea men p ecision in cance he apy [
160
]. In
ano he s udy, Sugimo o e al. (2017) employed me hac yla e-copolyme -based L o
con olled d ug deli e y. The L exhibi ed a igge ed elease o he d ug unde acidic
and ele a ed- empe a u e condi ions. The elease kine ics we e s udied by changing he
empe a u e and pH, showing ha he L eleased mo e d ug a pH 5.0 and 42
◦
C han a
physiological condi ions (pH 7.4 and 37
◦
C). The an i umo e icacy was e alua ed using
HeLa cells, demons a ing enhanced cy o oxici y unde dual-s imuli condi ions compa ed
o single s imuli. This wo k u he emphasizes he impo ance o p ecision in d ug elease
o a ge ed he apies, pa icula ly in ce ical cance ea men [161].
Ta e al. (2010) ad anced he ield by designing L unc ionalized wi h polyme ic
copolyme s o deli e ing Dox in a ge ing umo s. The eam syn hesized hese copolyme s
Pha maceu ics 2025,17, 245 21 o 36
using e e sible addi ion- agmen a ion chain ans e (RAFT) polyme iza ion, inco po-
a ing N-isop opylac ylamide (NIPAAm) and p opyl ac ylic acid (PAA) o impa dual
pH/ empe a u e esponsi eness. To assess he elease p ope ies, hese polyme -modi ied
L we e es ed o hei memb ane-dis up i e beha io unde modi ied pH and empe a-
u e condi ions, showing enhanced d ug elease p o iles. In addi ion, in se um s abili y
s udies, empe a u e-sensi i e L demons a ed signi ican ly lowe d ug leakage compa ed
o adi ional o mula ions, hus con i ming i s po en ial o educe colla e al damage o
heal hy issues du ing cance he apy [162].
S eal h L ha e been enginee ed o e ade immune ecogni ion and ex end he ci cula-
ion ime, he eby enhancing d ug accumula ion a umo si es. While PEGyla ion emains
he mos widely used s a egy o achie e his e ec [
163
], al e na i e app oaches ha e also
been explo ed. Zwi e ionic lipids, such as DPPC, ha e been epo ed o con e s eal h
p ope ies by educing p o ein adso p ion and minimizing ecogni ion by he MPS. Simila
o PEGyla ion, inco po a ing zwi e ionic lipids in o liposomal o mula ions has demon-
s a ed an inc ease in he sys emic ci cula ion ime [
164
]. Based on he use o zwi e ionic
lipids, Ga cía e al. (2021) in es iga ed he impac o CHOL le els on he pe o mance o
he mosensi i e L unc ionalized wi h gold nanopa icles (AuNPs) o con olled deli e y
o Dox. Two liposomal o mula ions, L1 (3.35 mol% CHOL) and L2
(40 mol% CHOL)
,
we e e alua ed. The L we e p epa ed using DPPC and didodecyldime hylammonium b o-
mide (DDAB), and Dox was loaded using a ansmemb ane pH-g adien me hod. AuNPs
we e elec os a ically ancho ed o he ca ionic liposomal su aces. The s udy e ealed
ha highe CHOL le els enhanced memb ane igidi y, educed L size, and inc eased
d ug encapsula ion e iciency.
In i o
Dox elease s udies demons a ed con olled d ug
elease, wi h highe empe a u es (42
◦
C) signi ican ly enhancing Dox di usion due o
inc eased memb ane pe meabili y. Func ionaliza ion wi h AuNPs u he imp o ed he -
mal esponsi eness and elease p o iles, pa icula ly o he L2 o mula ion. Cy o oxici y
assays in b eas (MDA-MB-231) and o a ian (SK-OV-3) cance cells con i med he sus-
ained an ip oli e a i e ac i i y o Dox-loaded L, wi h AuNPs-L2-Dox exhibi ing enhanced
he mosensi i i y. These indings highligh he po en ial o CHOL-modula ed, AuNP-
unc ionalized L o hype he mia-based cance he apy [
165
]. Addi ionally, Ga cía e al.
(2022) de eloped and e alua ed an inno a i e app oach using L composed o nucleolipids,
DPPC, and CHOL, which we e esponsi e o dual s imuli ( empe a u e and pH changes).
These L we e unc ionalized wi h PEGyla ed-AuNPs o enable a ge ed deli e y o Dox in
cance he apy. The Dox elease p o iles we e s udied unde a ious pH and empe a u e
condi ions, e ealing ha he L emained s able a physiological pH and empe a u e bu
showed a signi ican inc ease in d ug elease unde lowe pH and highe empe a u e,
con i ming hei dual sensi i i y. Addi ionally,
In i o
s udies on cellula up ake and
cy o oxici y in o a ian and b eas cance cells demons a ed enhanced an icance e icacy
o Dox-loaded L compa ed o ee Dox [166], as shown in Figu e 7.

Pha maceu ics 2025,17, 245 22 o 36
Pha maceu ics 2025, 17, x FOR PEER REVIEW 21 o 35
Cy o oxici y assays in b eas (MDA-MB-231) and o a ian (SK-OV-3) cance cells con-
i med he sus ained an ip oli e a i e ac i i y o Dox-loaded L, wi h AuNPs-L2-Dox ex-
hibi ing enhanced he mosensi i i y. These indings highligh he po en ial o CHOL-
modula ed, AuNP- unc ionalized L o hype he mia-based cance he apy [165]. Addi-
ionally, Ga cía e al. (2022) de eloped and e alua ed an inno a i e app oach using L
composed o nucleolipids, DPPC, and CHOL, which we e esponsi e o dual s imuli ( em-
pe a u e and pH changes). These L we e unc ionalized wi h PEGyla ed-AuNPs o enable
a ge ed deli e y o Dox in cance he apy. The Dox elease p o iles we e s udied unde
a ious pH and empe a u e condi ions, e ealing ha he L emained s able a physio-
logical pH and empe a u e bu showed a signi ican inc ease in d ug elease unde lowe
pH and highe empe a u e, con i ming hei dual sensi i i y. Addi ionally, In i o s ud-
ies on cellula up ake and cy o oxici y in o a ian and b eas cance cells demons a ed
enhanced an icance efficacy o Dox-loaded L compa ed o ee Dox [166], as shown in
Figu e 7.
Figu e 7. Rep esen a ion o Dox-loaded nucleolipid-based liposomes (L) unc ionalized wi h
PEGyla ed AuNPs, illus a ing hei dual sensi i i y o pH and empe a u e changes o con olled
Dox elease in acidic en i onmen s and hype he mia condi ions. Highligh ed p ope ies include
nanome ic size, uni o m size dis ibu ion, sphe ical s uc u e, nega i e ze a po en ial, efficien d ug
loading, and s able ancho ing o AuNPs ia elec os a ic in e ac ions. These L exhibi ed inc eased
he apeu ic efficacy agains b eas and o a ian cance cells. Dox: doxo ubicin; AuNPs: gold nano-
pa icles; DPPC: dipalmi oylphospha idylcholine; DG-CDP: 1,2-dipalmi oyl-sn-glyce o-3-(cy idine
diphospha e); Lip-Dox: nucleolipid-con aining Dox-loaded liposomes; PEG-AuNPs-Lip-Dox: NH2-
PEGyla ed AuNPs ancho ed on he su ace o Lip-Dox. Rep in ed wi h pe mission om Re . [166].
Expanding on combina ion he apies, Nezhadali e al. (2020) de eloped L o he co-
deli e y o Dox and mi omycin C, aiming o enhance he efficacy o combina ion chemo-
he apy. The L we e modi ied wi h a copolyme composed o NIPAAm o he mosensi-
i i y and PAA o pH sensi i i y. This o mula ion allowed con olled elease unde
mildly acidic condi ions (pH 5.5) and a ele a ed empe a u es (42 °C), eplica ing umo
mic oen i onmen s. In i o s udies wi h b eas cance cells (MCF-7) demons a ed ha
he co-loaded L exhibi ed signi ican ly highe cy o oxici y compa ed o ee d ug combi-
na ions, con i ming he po en ial o he sys em o imp o e cance ea men [167]. Fu -
he mo e, Zhao e al. (2020) de eloped L o he con olled elease o cy a abine, a chemo-
he apeu ic agen . The L we e composed o DPPC and CHOL, p o iding
Figu e 7. Rep esen a ion o Dox-loaded nucleolipid-based liposomes (L) unc ionalized wi h PEGy-
la ed AuNPs, illus a ing hei dual sensi i i y o pH and empe a u e changes o con olled Dox
elease in acidic en i onmen s and hype he mia condi ions. Highligh ed p ope ies include nanome -
ic size, uni o m size dis ibu ion, sphe ical s uc u e, nega i e ze a po en ial, e icien d ug loading,
and s able ancho ing o AuNPs ia elec os a ic in e ac ions. These L exhibi ed inc eased he apeu ic
e icacy agains b eas and o a ian cance cells. Dox: doxo ubicin; AuNPs: gold nanopa icles; DPPC:
dipalmi oylphospha idylcholine; DG-CDP: 1,2-dipalmi oyl-sn-glyce o-3-(cy idine diphospha e); Lip-
Dox: nucleolipid-con aining Dox-loaded liposomes; PEG-AuNPs-Lip-Dox: NH2-PEGyla ed AuNPs
ancho ed on he su ace o Lip-Dox. Rep in ed wi h pe mission om Re . [166].
Expanding on combina ion he apies, Nezhadali e al. (2020) de eloped L o he co-
deli e y o Dox and mi omycin C, aiming o enhance he e icacy o combina ion chemo he -
apy. The L we e modi ied wi h a copolyme composed o NIPAAm o he mosensi i i y
and PAA o pH sensi i i y. This o mula ion allowed con olled elease unde mildly acidic
condi ions (pH 5.5) and a ele a ed empe a u es (42
◦
C), eplica ing umo mic oen i on-
men s.
In i o
s udies wi h b eas cance cells (MCF-7) demons a ed ha he co-loaded L
exhibi ed signi ican ly highe cy o oxici y compa ed o ee d ug combina ions, con i ming
he po en ial o he sys em o imp o e cance ea men [
167
]. Fu he mo e, Zhao e al.
(2020) de eloped L o he con olled elease o cy a abine, a chemo he apeu ic agen . The
L we e composed o DPPC and CHOL, p o iding he mosensi i i y, while he exogenous
laye was unc ionalized wi h poly (aspa ic acid) g a ed wi h oc ylamine o pH sensi-
i i y. These dual-sensi i e L we e designed o inc ease elease cy a abine in esponse o
he acidic and hype he mal condi ions ypically ound in umo en i onmen s (pH 5.0
and
42 ◦C
).
In i o
expe imen s using HepG2 li e cance cells demons a ed ha he L
induced signi ican ly highe cy o oxici y unde hese dual-s imuli condi ions, compa ed o
he ee d ug and single-s imuli L. Addi ionally, he sys em showed minimal oxici y o
no mal hepa ocy e (L02) cells, indica ing i s po en ial o enhanced umo a ge ing wi h
educed side e ec s [168].
In pa allel, some L combine pH wi h enzyma ic esponsi eness, whe e enzymes o e -
exp essed in he umo mic oen i onmen igge s uc u al changes in he ca ie , leading
o selec i e d ug deli e y. Ge e al. (2024) de eloped a umo -speci ic liposomal nano eac o
sys em co-modi ied wi h human se um albumin and sialic acid, which was designed o
enhance coope a i e cance he apy. These nano eac o s we e ac i a ed in esponse o
acidic pH and o e exp essed enzymes wi hin he umo mic oen i onmen , igge ing
Pha maceu ics 2025,17, 245 23 o 36
a cascade o eac ions o imp o e he apeu ic selec i i y. The esea che s e alua ed he
biocompa ibili y o he se um albumin/sialic-acid-modi ied L
In i o
, obse ing educed
phagocy osis by immune cells.
In i o
s udies, whe e he L we e injec ed in o umo -
bea ing mice, demons a ed signi ican accumula ion a he umo si e compa ed o no mal
issues, indica ing enhanced umo a ge ing and imp o ed he apeu ic e icacy [
169
]. Also,
Liu e al. (2019) de eloped dual- esponsi e polyme -L designed o syne gis ic cance
ea men ia immuno-chemo he apy. These L espond o bo h he acidic pH o he umo
mic oen i onmen and umo -o e exp essed enzymes, igge ing he elease o Dox in a
con olled manne . The sys em enhances selec i e d ug deli e y and minimizes o - a ge
e ec s.
In i o
s udies demons a ed imp o ed cellula up ake and immune ac i a ion,
while
in i o
expe imen s in umo -bea ing mice showed signi ican umo accumula ion
and a po en an i umo esponse. These esul s highligh he po en ial o his sys em o
enhanced chemo he apy and immune modula ion in cance ea men [170].
Fu he ad ancemen s include sys ems ha in eg a e pH/ edox esponsi eness, le e -
aging he acidic ex acellula en i onmen and in acellula edox imbalances. These
ca ie s ensu e ha he elease occu s only wi hin speci ic cellula compa men s, enhanc-
ing he he apeu ic index. Zhang and Zhao (2011) in es iga ed a s a egy ha u ilized edox
and pH s imuli o igge d ug elease om L. They de eloped polyme ized L composed o
PEG, CHOL, and lipids con aining S-S bonds, which could be clea ed in esponse o edox
igge s. These L we e loaded wi h Dox and es ed o hei esponsi eness o edox and
pH changes.
In i o
expe imen s showed highe elease unde educing condi ions and a
lowe pH le els. Addi ionally, hese L e ec i ely a ge ed and elimina ed cance cells while
minimizing e ec s on heal hy cells. Recen ad ances in he de elopmen o dual pH/ edox-
esponsi e nanoca ie s highligh he con inuous p og ess in enhancing a ge ed d ug
deli e y sys ems o in lamma ion ea men and cance he apy [
171
]. Ma uso e al. (2016)
ocused on a dual nanoliposomal complex ha inco po a ed coppe -ligand coo dina ion
o ch onic in lamma ion ea men . Thei o mula ion u ilized Eud agi
®
E100-cys amine
and phospholipids o enable he con olled elease o a coppe -liganded bioac i e complex,
speci ically p ednisolone succina e. This design allowed he L o elease hei he apeu ic
payload in esponse o he unique acidic and educ i e condi ions ound in in lamed issues.
In i o
s udies e ealed ha hese coppe -ligand L exhibi ed po en an i-in lamma o y
e ec s by egula ing c i ical mechanisms in ol ed in in lamma ion. Mo eo e ,
in i o
expe imen s using in lamma ion-induced animal models demons a ed a signi ican educ-
ion in in lamma o y ma ke s and issue damage when ea ed wi h his bioac i e complex,
unde sco ing i s he apeu ic po en ial in ch onic in lamma o y condi ions [
172
]. Expanding
on hese de elopmen s, Li e al. (2019) in oduced a pH/ edox- esponsi e sup amolecula
s uc u e (Pep-V
⊂
P-PEG) designed o enhance in e ac ions wi h lipid memb anes in cance
he apy. This sys em inco po a ed a pep ide modi ied wi h iologen (Pep-V) and PEG-
pilla [5]a ene as a p o ec i e “helme ”. The a chi ec u e allowed he complex o modula e
i s con o ma ion in esponse o he acidic and educ i e condi ions p e alen in umo
en i onmen s. They p epa ed L using neu al DPPC o ep esen no mal cell memb anes
and nega i ely cha ged 1,2-dipalmi oyl-sn-glyce o-3-phospha e (DPPG) o model umo
cell memb anes. The esul s indica ed ha Pep-V demons a ed signi ican in e ac ions
wi h lipid memb anes, enhancing s abili y a acidic pH while e ec i ely des abilizing
memb anes upon exposu e o educing agen s, like sodium hiosul a e (Na
2
S
2
O
3
). Al-
hough his sys em did no ca y a con en ional chemo he apeu ic agen , i s design aimed
o imp o e he deli e y and e icacy o exis ing ea men s h ough a ge ed memb ane
dis up ion [173].
Mo e ecen ly, Zhao e al. (2022) designed a pH/ edox-sensi i e cascade liposomal
sys em using PEGyla ed glucose and TPP as a ge ing moie ies o co-deli e y o a p od ug
Pha maceu ics 2025,17, 245 24 o 36
o Dox and LND (Dox-LND@pH- edox-L) speci ically a ge ing glioma. This inno a i e
sys em was enginee ed o elease i s he apeu ic ca go in he umo mic oen i onmen un-
de acidic and educ i e condi ions, signi ican ly imp o ing d ug ac i a ion and a ge ing
speci ici y, as shown in Figu e 8. The esea che s conduc ed
in i o
e icacy e alua ions,
demons a ing a ma ked inc ease in selec i e d ug elease and cy o oxici y in glioma cells.
Fu he mo e,
in i o
s udies using glioma-bea ing mice con i med ha he Dox-LND@pH-
edox-L accumula ed p e e en ially a he umo si e, esul ing in signi ican umo g ow h
inhibi ion, and minimized o - a ge e ec s compa ed o non- a ge ed o mula ions. To-
ge he , hese s udies ep esen a signi ican p og ession in he ield o esponsi e nanoca ie
sys ems, highligh ing he po en ial o imp o ed ea men e icacy and a ge ing speci ici y
in bo h cance he apy and in lamma ion managemen [174].
Pha maceu ics 2025, 17, x FOR PEER REVIEW 23 o 35
in oduced a pH/ edox- esponsi e sup amolecula s uc u e (Pep-V⊂P-PEG) designed o
enhance in e ac ions wi h lipid memb anes in cance he apy. This sys em inco po a ed a
pep ide modi ied wi h iologen (Pep-V) and PEG-pilla [5]a ene as a p o ec i e “helme ”.
The a chi ec u e allowed he complex o modula e i s con o ma ion in esponse o he
acidic and educ i e condi ions p e alen in umo en i onmen s. They p epa ed L using
neu al DPPC o ep esen no mal cell memb anes and nega i ely cha ged 1,2-dipal-
mi oyl-sn-glyce o-3-phospha e (DPPG) o model umo cell memb anes. The esul s indi-
ca ed ha Pep-V demons a ed signi ican in e ac ions wi h lipid memb anes, enhancing
s abili y a acidic pH while effec i ely des abilizing memb anes upon exposu e o educ-
ing agen s, like sodium hiosul a e (Na₂S₂O₃). Al hough his sys em did no ca y a con-
en ional chemo he apeu ic agen , i s design aimed o imp o e he deli e y and efficacy
o exis ing ea men s h ough a ge ed memb ane dis up ion [173].
Mo e ecen ly, Zhao e al. (2022) designed a pH/ edox-sensi i e cascade liposomal
sys em using PEGyla ed glucose and TPP as a ge ing moie ies o co-deli e y o a p o-
d ug o Dox and LND (Dox-LND@pH- edox-L) speci ically a ge ing glioma. This inno-
a i e sys em was enginee ed o elease i s he apeu ic ca go in he umo mic oen i on-
men unde acidic and educ i e condi ions, signi ican ly imp o ing d ug ac i a ion and
a ge ing speci ici y, as shown in Figu e 8. The esea che s conduc ed in i o efficacy
e alua ions, demons a ing a ma ked inc ease in selec i e d ug elease and cy o oxici y
in glioma cells. Fu he mo e, in i o s udies using glioma-bea ing mice con i med ha
he Dox-LND@pH- edox-L accumula ed p e e en ially a he umo si e, esul ing in sig-
ni ican umo g ow h inhibi ion, and minimized off- a ge effec s compa ed o non- a -
ge ed o mula ions. Toge he , hese s udies ep esen a signi ican p og ession in he ield
o esponsi e nanoca ie sys ems, highligh ing he po en ial o imp o ed ea men e -
icacy and a ge ing speci ici y in bo h cance he apy and in lamma ion managemen
[174].
Figu e 8. The syne gis ic an i-glioma p ocess o doxo ubicin (Dox) p od ugs and lonidamine (LND)
co-loaded in pH- edox- esponsi e cascade- a ge ed liposomes modi ied wi h glucose and TPP
Figu e 8. The syne gis ic an i-glioma p ocess o doxo ubicin (Dox) p od ugs and lonidamine (LND)
co-loaded in pH- edox- esponsi e cascade- a ge ed liposomes modi ied wi h glucose and TPP ( iph-
enylphosphonium). BBB: blood–b ain ba ie ; GLUT1: glucose anspo e s; GSH: glu a hione; S-S:
disul ide bonds; PEG: polye hylene glycol. Rep in ed wi h pe mission om Re . [174].
Con inuing along his g adien o s imuli, he in e ac ion be ween edox and ROS-
esponsi e L p o ides ano he le el o con ol, such as oxida i e s ess wi hin umo cells,
which can se e as a powe ul igge o d ug elease. Xue e al. (2022) designed Fe
3+
-
media ed L co-loaded wi h shikonin and py opheopho bide-a (PPA) o induce obus
immunogenic cell dea h by in eg a ing ROS enhancemen and GSH deple ion, esponding
o oxida i e s ess and edox imbalances in he umo mic oen i onmen . These esea che s
incuba ed he Fe
3+
/shikonin/PPA-loaded L wi h 4T1 b eas cance cells o e alua e hei
in acellula ROS p oduc ion, showing a signi ican ROS inc ease while simul aneously
educing GSH. Fu he mo e, o analyze he
in i o
an i umo e icacy, hese L we e injec ed
in o 4T1 umo -bea ing mice, and he esul s showed signi ican umo g ow h inhibi ion.
T ea ed mice exhibi ed enhanced immunogenic cell dea h ma ke s, such as cal e iculin
exposu e and ATP elease, highligh ing he po en an i umo immune esponse igge ed
by his dual-s imuli liposomal sys em [175].
Pha maceu ics 2025,17, 245 25 o 36
Simila ly, ROS/glucose- esponsi e L ake ad an age o he me abolic al e a ions
in umo s, whe e ele a ed glucose up ake and oxida i e s ess ac as dual igge s o
con olled elease. Zhang e al. (2018) de eloped glucose/oxygen-exhaus ing L o com-
bined cance me abolism inhibi ion and hypoxia-ac i a ed he apy. These L encapsu-
la ed GOx and he hypoxia-ac i a ed p od ug AQ4N (banoxan one dihyd ochlo ide),
o mula ed om DPPC, CHOL, and DSPE-mPEG5k (PEG5k-conjuga ed dis ea oilphos-
pha idyle hanolamine), achie ing an a e age size o app oxima ely 100 nm. The L-GOx
e ec i ely ca alyzed he con e sion o glucose and oxygen in o gluconic acid and H
2
O
2
,
inc easing oxida i e s ess in cance cells.
In i o
s udies in 4T1 umo -bea ing mice demon-
s a ed ha L-GOx and L-AQ4N exhibi ed p olonged blood ci cula ion and signi ican
umo accumula ion. No ably, L-GOx educed in a umo al oxygen le els, enhancing hy-
poxia ma ke s. The combina ion o hese he apies led o supe io umo g ow h inhibi ion,
unde sco ing he po en ial o his dual app oach o e ec i e cance ea men [176].
The e sa ili y o hese sys ems becomes e en mo e appa en when mul iple ypes o
s imuli a e in eg a ed. While mos epo ed pla o ms espond o wo endogenous igge s,
he combina ion o endogenous and exogenous s imuli o e s addi ional laye s o con ol.
These mul i-s imuli sys ems combine endogenous cues, such as pH, empe a u e, o edox
po en ial, wi h exogenous igge s like ligh o magne ic ields, u he enhancing d ug
elease p ecision. Yao e al. (2021) explo ed he de elopmen o hyb id L ha a e iple-
esponsi e and designed o a ge ed umo diagnosis and ea men , wi h s ong magne ic
esonance imaging capabili ies. They c ea ed bo h anisamide-modi ied and non-modi ied
molecules esponsi e o UV ligh and GSH, as well as celecoxib-modi ied and non-modi ied
molecules esponsi e o UV ligh and H
2
O
2
. The inal o mula ion o hese UV/GSH/H
2
O
2
iple- esponsi e L was achie ed by combining he molecules (10,10-NB-S-S-P-AA and
10,10-NB-OA-P-CE) wi h a con as agen (12,12-NB-DTPA-Gd). The esul ing sys em
displayed excellen d ug encapsula ion e iciency, along wi h good s abili y and biocom-
pa ibili y, while also deli e ing ou s anding magne ic esonance imaging pe o mance.
Unde condi ions simula ing low pH, H
2
O
2
, and GSH, he L eleased up o 80% o he
encapsula ed d ug. Mo eo e , he d ug-loaded L exhibi ed e ec i e a ge ing o umo
cells. O e all, his iple- esponsi e L sys em shows po en ial as a p omising app oach o
umo he anos ics [177].
Al e na i ely, To es e al. (2025) in es iga ed he imp o emen o AuNPs’ unc ional-
iza ion on Dox-loaded L using quali y-by-design ools. They explo ed a ange o a iables
ha in luence he p ope ies o he inal sys em, AuNPs-L-Dox, and es ablished op imized
condi ions o imp o e he in e acial cha ac e is ics and maximize Dox encapsula ion e i-
ciency.
In i o
expe imen s demons a ed ha Dox elease was e ec i ely con olled by
pH a ia ions and hea gene a ed om ligh exposu e, wi h a no able inc ease in he elease
unde acidic condi ions and du ing op ical hype he mia. The AuNPs-L-Dox showed
signi ican an i umo ac i i y agains he SK-OV-3 o a ian cance cell line, demons a ing a
esponse ha was bo h dependen on he d ug concen a ion and in luenced by i adia ion-
induced empe a u e changes. Sa e y e alua ions in HaCaT ke a inocy e cells indica ed
ha he biocompa ibili y o AuNPs-L-Dox was compa able o ha o ee Dox [178].
Simila ly, ackable L ha e eme ged as p omising dual- unc ion sys ems, in eg a ing
diagnos ic and he apeu ic capabili ies o ad ance pe sonalized ea men s. Fo ins ance,
Li e al. (2024) syn he ized pH/oxygen/pho o he mal-sensi i e L o diagnose solid umo s
in he ea ly s age. These L we e syn hesized using a pH-sensi i e amphiphilic u henium
complex, which ac s as an oxygen-sensi i e luo escen p obe, co-assembled wi h lipids o
encapsula e indocyanine g een (ICG) as a pho o he mal agen . The L exhibi ed enhanced
umo de ec ion h ough oxygen concen a ion moni o ing and adiome ic imaging, which
dis inguished umo si es based on hypoxia. Unde nea -in a ed (NIR) ligh , he L acili-
Pha maceu ics 2025,17, 245 32 o 36
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