Polymer-based nanocarriers to transport therapeutic biomacromolecules across the blood-brain barrier

Re iew a icle
Polyme -based nanoca ie s o anspo he apeu ic biomac omolecules
ac oss he blood-b ain ba ie
Elena Rome o-Ben
a
, Upashi Goswami
a,b
, Jackeline So o-C uz
a
,
Ami eza Mansoo i-Ke mani
b,c,d
, Dhi aj Mish a
a,e
, Se gio Ma in-Salda˜
na
a
,
Jone Mu˜
noz-Uga emendia
b
, Alejand o Sosnik
e
, Ma celo Calde ´
on
a,
, Ana Beloqui
a,
,
Ai o La a˜
naga
b,*
a
POLYMAT, Applied Chemis y Depa men , Facul y o Chemis y, Uni e si y o he Basque Coun y UPV/EHU, Paseo Manuel de La dizabal 3, Donos ia-San Sebas i´
an
20018, Spain
b
Depa men o Mining-Me allu gy Enginee ing and Ma e ials Science, POLYMAT, Bilbao School o Enginee ing, Uni e si y o he Basque Coun y (UPV/EHU), Plaza
To es Que edo 1, Bilbao 48013, Spain
c
Is i u o I aliano di Tecnologia, Sma Bio-In e aces, Viale Rinaldo Piaggio 34, Pon ede a 56025, I aly
d
Scuola Supe io e San ’Anna, The Bio obo ics Ins i u e, Viale Rinaldo PIaggio 34, Pon ede a 56025, I aly
e
Labo a o y o Pha maceu ical Nanoma e ials Science, Depa men o Ma e ials Science and Enginee ing, Technion - Is ael Ins i u e o Technology, Hai a 3200003,
Is ael
IKERBASQUE, Basque Founda ion o Science, Plaza Euskadi 5, Bilbao 48009, Spain
ARTICLE INFO
Keywo ds:
Biomac omolecules
Blood-b ain ba ie anspo
Polyme ic nanopa icles
Neu ological diso de s
ABSTRACT
The apeu ic biomac omolecules such as gene ic ma e ial, an ibodies, g ow h ac o s and enzymes ep esen a
no el he apeu ic al e na i e o neu ological diseases and diso de s. In compa ison o adi ional he apeu ics,
which a e mainly based on small molecula weigh d ugs ha add ess he symp oms o hese diso de s, he a-
peu ic biomac omolecules can educe undesi ed side e ec s and a ge speci ic pa hological pa hways, hus
pa ing he way owa ds pe sonalized medicine. Howe e , hese biomac omolecules unde go deg ada ion/
dena u a ion p ocesses in he physiological en i onmen and show poo capaci y o c oss he blood-b ain ba ie
(BBB). Consequen ly, hey a ely each he cen al ne ous sys em (CNS) in hei ac i e o m. He ein, we c i -
ically o e iew se e al polyme ic nanoca ie s ha can p o ec and deli e he apeu ic biomac omolecules
ac oss he BBB. Polyme ic nanoca ie s a e i s ca ego ized based on hei a chi ec u e (biodeg adable solid
nanopa icles, nanogels, dend ime s, sel -assembled nanopa icles) ha ul ima ely de e mines hei physico-
chemical p ope ies and unc ion. The a ailable polyme ic o mula ions a e hen ho oughly analyzed, placing
pa icula a en ion on hose s a egies ha ensu e he s abili y o he biomac omolecules du ing hei encap-
sula ion p ocess and p omo e hei passage ac oss he BBB by con olling hei physical (e.g., mechanical
p ope ies, size, su ace cha ge) and chemical (e.g., su ace unc ional g oups, a ge ing mo i s) p ope ies.
Acco dingly, his e iew gi es a unique pe spec i e on polyme ic nanoca ie s o he deli e y o he apeu ic
biomac omolecules ac oss he BBB, ep esen ing a concise, comple e and easy- o- ollow guide, which will be o
high in e es o chemis s, ma e ial scien is s, pha macologis s, and biologis s. Besides, i also p o ides a c i ical
pe spec i e abou he limi ed clinical ansla ion o hese sys ems.
S a emen o signi icance: The inc easing incidence o cen al ne ous sys em diso de s is a majo heal h conce n.
The use o he apeu ic biomac omolecules has been placed in he spo ligh o many in es iga ions. Howe e ,
eaching he apeu ic concen a ion le els o biomac omolecules in he cen al ne ous sys em is es ic ed by he
blood-b ain ba ie and, hus, his ep esen s he main clinical challenge when de eloping e icien he apies.
He ein, we p o ide a c i ical discussion abou he use o polyme ic nanoca ie s o deli e he apeu ic bio-
mac omolecules in o he cen al ne ous sys em, highligh ing po en ial u u e di ec ions o o e come he cu en
challenges.
* Co esponding au ho .
E-mail add ess: [email p o ec ed] (A. La a˜
naga).
Con en s lis s a ailable a ScienceDi ec
Ac a Bioma e ialia
jou nal homepage: www.else ie .com/loca e/ac bio
h ps://doi.o g/10.1016/j.ac bio.2025.02.065
Recei ed 16 Sep embe 2024; Recei ed in e ised o m 20 Feb ua y 2025; Accep ed 28 Feb ua y 2025
Ac a Bioma e ialia 196 (2025) 17–49
A ailable online 1 Ma ch 2025
1742-7061/© 2025 The Au ho s. Published by Else ie Inc. on behal o Ac a Ma e ialia Inc. This is an open access a icle unde he CC BY-NC-ND license
(
h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/ ).
1. In oduc ion
In he las hi y yea s, he e has been a subs an ial ise in he global
occu ence and dea h a es associa ed o neu ological diso de s,
cu en ly ep esen ing a majo cause o mo bidi y and mo ali y
wo ldwide. This phenomenon can be asc ibed o he expansion and
ma u a ion o he wo ld popula ion, along wi h inc easing ulne abili y
o en i onmen al, me abolic, and li es yle haza ds. Acco ding o he
“Global Bu den o Disease, Inju ies, and Risk Fac o s S udy (GBD) 2021
″
,
a ound 3.4 billion people wo ldwide expe ienced a ne ous sys em
diso de in 2021 [1]. These include, among o he s: (i) neu odegene a-
i e diseases, namely Alzheime ’s disease (AD), Pa kinson’s disease
(PD), and Hun ing on’s disease (HD); (ii) au oimmune diseases like
mul iple scle osis (MS); (iii) b ain cance , pa icula ly glioblas oma
mul i o me (GBM); (i ) ce eb o ascula acciden s (e.g., ischemic
s oke); ( ) auma ic b ain inju y (TBI); and ( i) o he diseases (e.g.,
epilepsy, ansien ischemic a ack, and ce eb al palsy) a ec ing he
cen al ne ous sys em (CNS). In he u u e, i is an icipa ed ha b ain
diso de s will eme ge as a signi ican global heal h conce n, posing
subs an ial mo ali y a es and inancial bu dens [2].
To ace his challenge, g ea e o s a e being cu en ly in es ed in
de eloping ea men s ha no only alle ia e he symp oms o hese
diseases bu also ea he unde lying pa hology. Se e al ac o s
con ibu e o he ailu e o cu en medica ion ea men s (mainly based
on small molecula weigh (MW) d ugs) o b ain diseases, including he
equi emen o la ge he apeu ic doses and p olonged and highly
in asi e in a en icula injec ions [3]. These a iables s ongly impac
he medioc e esul s e ealed by s anda d ea men op ions in he clinic
[4,5]. The use o biomac omolecules such as oligopep ides, monoclonal
an ibodies, g ow h ac o s, an ioxidan enzymes o nucleic acids, ep-
esen s a no el he apeu ic al e na i e and has ga ne ed conside able
a en ion om esea che s, p omp ing ex ensi e endea o s o acili a e
hei ansla ion in o clinical applica ions. This new class o he apeu ics
o e s highe speci ici y and can g ea ly educe o - a ge e ec s
(Table 1).
Al hough signi ican ad ances in molecula biology pe mi s now he
la ge-scale syn hesis o such delica e biomac omolecules, hei use as a
he apy s ill aces unme challenges. The cell memb ane has e ol ed
o e billions o yea s o accu a ely con ol he mo emen o molecules
in o and ou o he cy osol, p o ec ing he in acellula en i onmen
om ex acellula dis u bance. Hence, he high MW and he hyd ophilic
na u e o mos o he biomac omolecules esul s in a limi ed pe me-
abili y h ough biological ba ie s like cell memb anes [29]. Besides,
mac omolecula s uc u es can unde go con o ma ional changes due o
he dis up ion o na i e non-co alen in e ac ions and he clea age o
pep ide bonds, esul ing in impai ed he apeu ic agen s. Fu he mo e,
deli e ing biomac omolecules o he b ain sys emically aces di e se
challenges such as: insu icien d ug adminis a ion, deg ada-
ion/dena u a ion in he bloods eam, i s -pass clea ance, immune
esponse, oxici y o no mal issues, and es ic ions imposed by he
blood-b ain ba ie (BBB); mos o he biomac omolecules a e unable o
nonin asi ely c oss he BBB and en e he b ain pa enchyma [30].
The seek o s a egies o he e icien espassing o bio-
mac omolecules h ough he BBB has opened new esea ch oppo u-
ni ies in which s a e-o - he-a echnologies a e me ged wi h enginee ed
deli e y sys ems. Thus, new app oaches encompass he dis up ion o he
BBB ia he u iliza ion o magne ic esonance-guided ocused ul asound
[31] o he lipidiza ion o wa e -soluble d ugs [32]. In his ega d,
nano echnology could p o ide sophis ica ed s a egies o design and
o mula e nanoma e ials loaded wi h biomolecules, signi ican ly
enhancing pa ien p ospec s and achie ing posi i e pha maco-economic
esul s [33,34]. A clea example is he applica ion o an ioxidan s [35] in
he managemen o b ain inju ies and neu odegene a ion, whe ein
an ioxidan enzymes such as supe oxide dismu ase (SOD1) migh
Table 1
Cu en medica ions and biomac omolecules unde esea ch o he ea men o CNS diso de s o b ain cance [3].
Neu ological
diso de
Cha ac e is ic Cu en medica ions Common side e ec s S udies wi h biomac omolecules
Alzheime ’s
disease (AD)
G adually ad ancing demen ia
accompanied by memo y impai men .
Cholines e ase inhibi o s, NMDA
an agonis s.
Nausea, omi ing,
dia hea, dec eased
appe i e, dizziness,
headache, con usion.
Monoclonal an ibody agains Aβ agg ega es
[6] (Aducanumab [7], Lecanemab [8] and
Donanemab [9]).
Pa kinson´s
disease (PD)
Pa hological degene a ion o
nig os ia al dopamine neu ons
cha ac e ized by mo o igidi y, es ing
emo , and b adykinesia.
Le odopa, dopamine agonis ,
Monoamine oxidase-B inhibi o s,
ca echol o-me hyl ans e ase (COMT)
inhibi o s, su gical he apies.
Dyskinesias, nausea,
omi ing, o hos a ic
hype ension,
hallucina ions, li e
damage, in ec ions.
Neu o ophic ac o s (glial cell-de i ed
neu o ophic ac o (GDNF) and b ain-
de i ed neu o ophic ac o (BDNF)) [10,11],
monoclonal an ibodies agains
α
-synuclein
(Snca) (P asinezumab) [12,13], shRNA
a ge ing Snca [14].
Hun ing on’s
disease (HD)
Au osomal neu odegene a i e
diso de . Pa ien s exhibi a ange o
symp oms, including cho ea, men al
dis u bances, and cogni i e
de e io a ion.
Cho ea and an ipsycho ic medica ion,
an idep essan s (Selec i e se o onin
eup ake inhibi o s), mood s abilize s.
D owsiness,
pa kinsonism, dep ession,
insomnia, anxie y,
aka hisia, excess weigh
gain and dyslipidemia.
Di alen small in e e ing RNA (siRNA)
silencing he hun ing in gene [15].
Chape one p o eins o comba he
neu odegene a i e e ec [16].
Mul iple
scle osis
(MS)
Demyelina ing disease cha ac e ized
by he immune sys em’s a ack on he
myelin shea h su ounding ne e
ibe s, esul ing in communica ion
impai men s be ween he b ain and he
body.
gamma-aminobu y ic acid analogs,
ac i a ion o
α
2-ad ene gic ecep o s,
mi ochond ial dihyd o-o o a e
dehyd ogenase (DHODH) inhibi o s,
immunomodula o s (Gla i ame
ace a e).
Dia hea, nausea, li e
p oblems, weakness,
hallucina ions,
hypo ension, inc eased
isk o in ec ions.
Neu o ophic ac o s (BDNF) [17].
Remyelina ion-p omo ing p o eins
(Insulin-like g ow h ac o 1 (IGF-1)) [18].
Monoclonal an ibodies (Na alizumab) [19].
S oke Neu ological de iciency a ibu ed o a
se e e ocal lesion o he cen al
ne ous sys em (CNS) due o a ascula
disease, including ce eb al in a c ion,
suba achnoid hemo hage (SAH), and
in ace eb al hemo hage (ICH).
Se ine p o ease issue- ype plasminogen
ac i a o .
Nausea, omi ing,
hypo ension, dizziness,
alle gic eac ions.
Neu o ophic ac o s (NGF) [20]. RNAi
a ge ing umo nec osis ac o (TNF)-
α
o
in e leukin (IL)-1β o educe pos -ischemic
in lamma ion [21]. miR-124, which
p omo es human neu ogenesis [22]. siRNAs
a ge ing caspase [23].
Glioblas oma Mos common and agg essi e umo
among glial neoplasms.
Radia ion he apy, emozolomide
adminis a ion (chemo he apy DNA
base alkyla ion), and su ge y.
Ce eb al edema,
con ulsions, a igue,
omi ing, skin damage,
alopecia, bone ma ow
supp ession.
Monoclonal an ibodies: Be acizumab ha
selec i ely binds o ascula endo helial
g ow h ac o (VEGF) [24], Ce uximab and
Pani umumab ha a ge he mu a ed
epide mal g ow h ac o ecep o (EGFR) III
a ian , common in glioblas oma [25,26],
siRNA agains Bcl-2 [27] o miR-124 [28].
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
18
assume a pi o al ole. None heless, due o hei limi ed s abili y and
adminis a ion, he li e a u e lacks ele an s udies. The po en ial o
clinical ans e a ises solely when u ilized in conjunc ion wi h nano-
ca ie s [36–38].
O e he yea s, signi ican ad ancemen s ha e been made in he
de elopmen o ailo ed nanoca ie s, wi h special a en ion o lipid
nanopa icles as deli e y sys ems o enhance he e ec i eness o hese
he apeu ics [39–41]. Howe e , he body ecognizes hese nanopa icles
as o eign ma e ials and ac i a es he inna e immuni y, he eby in lu-
encing adap i e immuni y [42]. In such si ua ions, polyme nano-
pa icles may o e supe io cha ac e is ics such as educed
immunogenici y, inc eased s abili y, and enhanced ep oducibili y
[43–45]. In e es ingly, hese p omising nanoca ie s, when combined
wi h cell-pene a ing echniques, can add ess he challenges associa ed
wi h he deli e y o biomac omolecules o he ea men o CNS dis-
o de s [46,47].
In his e iew, we emphasize he sophis ica ed a chi ec u es a ail-
able in he ecen li e a u e (i.e., ~60% o he e e ences used in his
e iew belong o s udies pe o med in he las 5 yea s) o he ab ica ion
o polyme ic nanoca ie s capable o c ossing he BBB om he blood-
s eam, oge he wi h he cu en app oaches o encapsula ing he a-
peu ic biomac omolecules (Fig. 1). This e iew does no aim solely o
p o ide examples o polyme ic nanoca ie s ha deli e bio-
mac omolecules ac oss he BBB, which a e summa ized in Table 2.
Ins ead, ou goal is o o e a c i ical pe spec i e on he ea u es ha
make hese polyme ic nanoca ie s ideal o his pu pose, as well as o
Fig. 1. Gene al illus a ion ha summa izes he main polyme ic nanoca ie s desc ibed in his e iew o anspo he apeu ic biomac omolecules in o he b ain. (A)
Biodeg adable solid nanopa icles encompass nanopa icles ha p esen (i) a b oad o syn he ic al e na i es o deco a e hei su ace wi h speci ic ligands o enhance
an ac i e a ge deli e y, and (ii) allow wo main encapsula ion app oaches, such as double wa e in-oil-wa e o nanop ecipi a ion echniques o encapsula e
biomac omolecules. (B) Nanogels a e so polyme ic nanopa icles, ha (i) pe mi he use o a b oad mul i- esponsi e c osslinke s o lead di e en s imuli- esponsi e
nanoma e ials and also (ii) allow he encapsula ion o biomac omolecules media ed by di e en echniques such as he o ma ion o sel -assembled complex, UV
polyme iza ion in liposomes, a om ans e adical polyme iza ions (ATRP) in in e se micelles and in si u adical polyme iza ion leading single enzyme nanogels. (C)
Dend i ic polyme s ha e a con olled syn hesis in mul i-b anched a chi ec u es, ha opens he possibili y o expose mul i alen ly speci ic g oups on hei su ace o
enhance ligand- ecep o s in e ac ions, and, a he same ime, modula e he su ace cha ge o encapsula e biomac omolecules as nucleic acids by elec os a ic
in e ac ion inside hei in e nal po es. (D) Sel -assembled polyme ic nanopa icles can be syn he ized h ough spon aneous in e ac ion o molecules (physic o ces) o
o m o ganized s uc u es ha acili a e he implemen a ion o encapsula ion app oaches. Bio ende has been used o c ea ing he desc ip i e image.
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
19
highligh he ad an ages o using ce ain ypes o polyme ic sys ems
o e o he s. Addi ionally, i highligh s clinical ansla ion, explo es
cu en challenges, and o e s insigh s in o u u e p ospec s in his ield.
This app oach allows he eade o d aw hei own conclusions,
conside ing ha each nanosys em possesses impo an ea u es o
di e en po en ial applica ions.
2. The blood-b ain ba ie issue o he apy design
2.1. Physiology o he blood-b ain ba ie
The BBB se es as a p o ec i e, semi-pe meable memb ane ha
in ica ely egula es he exchange o essen ial nu ien s, oxygen, and
ions om he bloods eam in o he CNS, while i p e en s he in ac ion
by exogenous subs ances, oxins, and pa hogens [69,70]. Ana omically,
he BBB is a complex and in eg a ed ne wo k o endo helial, neu al, and
immune cells, known as he neu o ascula uni [71–73]. The endo helial
cells, ep esen ing he main componen o he BBB, o m he inne line o
b ain capilla y walls wi h la ges su ace a ea. They a e pola ized wi h
nega i e su ace cha ge and no enes a ions, p e en ing he apid
di usion and exchange o nega i ely-cha ged molecules be ween he
blood and he b ain [69,70]. P ima ily, endo helial cells a e allied wi h
one ano he by igh junc ions (TJs), which is dis inc i e o endo helial
cells o CNS along wi h adhe ens junc ion, which oge he o m a obus
physical ba ie [72]. Unde he endo helial cells lies he basemen
memb ane. I consis s o ex acellula ma ix p o eins like collagen,
hepa in, laminin, nidogen, and pe lecan [69,70,72,73]. Wi hin he
basemen memb ane, pe icy es (a ype o mu al cells) g ow abluminal o
endo helial cells, and co e 90% o capilla y beds [73]. Pe icy es a e
esponsible o main aining he diame e o he essels and egula e he
speci ic gene exp ession o endo helial cells om BBB, essen ial o
main aining he TJs [71,74]. Due o hei close associa ion wi h endo-
helial cells, hey play a pi o al ole in egula ing BBB in eg i y, ho-
meos asis, and in con olling ce eb al blood low in capilla ies along
wi h exchange o ions and me aboli es be ween hem [69,75,76].
Addi ionally, hey a e also impo an in ascula de elopmen , egula-
ion o in lamma o y esponse by con olling leucocy e in il a ion,
sec e ion o in lamma o y media o s, and neu o oxin emo al [75,76].
A he in e ace be ween neu ons and endo helial cells a e he as o-
cy es, a ype o glial cells connec ed wi h he end walls o endo helium.
They co e mos o he CNS and gi e in eg i y by s eng hening he TJs,
while p o iding biological suppo o he cells [69,71]. They play a
majo ole in egula ion o ascula unc ion, exp ession o anspo e s
such as P-glycop o ein (P-gp) and glucose anspo e -1 (GLUT-1), wa e
and ion homeos asis, pH egula ion, neu o ascula coupling (as as o-
cy es a e he cen al link be ween mic o ascula u e and neu al
ne wo k), and p o ide ene gy- ich subs a es and insula ion o he
neu ons [70,71,76]. Acco dingly, close associa ion o as ocy es wi h
endo helial cells and pe icy es holds con ol o e pe meabili y ac oss
he BBB [69,77]. Mic oglia ac s as he mac ophages o he CNS,
mig a ing o pa hologically a ec ed egions o phagocy ose ne ous
issue [77]. Mic oglia a e igilan , and ensu e p ope esponse o any
Table 2
Polyme -based nanoca ie s ha anspo he apeu ic biomac omolecules ac oss he BBB o ea CNS diso de s o b ain cance .
Classi ica ion D ug deli e y sys em Ca go Disease BBB Pene a ion Re e ence
Biodeg adable solid
nanopa icles
(NPs)
Poly(lac ic-co-glycolic acid) PLGA NPs Enzyme galac osylce amidase K abbe disease Angiopep-2 (Ang2), g7 and
ans e in (T ).
[48]
PLGA NPs Small in e e ing RNA (siRNA) T auma ic b ain
inju y
Polyso ba e 80, poloxame 188,
DSPE- PEG-glu a hione, and
DSPE-PEG-T .
[49]
PLGA NPs Vi amin D-binding p o ein Alzheime ´s Disease
(AD)
- [50]
PLGA NPs Epide mal g ow h ac o
ecep o siRNA
Gliomas Ang2. [51]
Nanogels PLA-PEG-PLA NGs Ri uximab (RTX) Non-Hodgkin
lymphoma
2-me hac yloyloxye hyl
phospho ylcholine (MPC).
[52]
PLA-PEG-PLA NGs Ne e g ow h ac o and RTX Cen al ne ous
sys em (CNS)
diseases
MPC. [53]
Poly(N-(3-aminop opyl) me hac ylamide-
co-me hac yloyloxy e hyl
phospho ylcholine) and MMP sensi i e
pep ide sequence as c osslinke
Nimo uzumab and as uzumab B ain umo s MPC. [54,55]
Poly(e hylene glycol)-b-poly(me hac ylic
acid) (PEG-b-PMAA) diblock copolyme
Cispla in T ea men o glioma Monoclonal an ibodies agains
Cx43 and BSAT1.
[56]
Dend i ic polyme s Polyamidoamine dend ime Heme oxygenase-1 (HO-1)
plasmid
In lamma o y
diseases including
ischemic s oke
- [57]
Dend i ic polyglyce ol sul a e.
Dend i ic polyglyce olamine.
Pep idomime ic o he an i-
angiogenic p o ein
h ombospondin-1 (TSP-1 PM)
mic oRNA-34a (miR-34a)
Glioblas oma
Glioma
T . [58,59]
Ca bosilane dend ime . Lac o e in bea ing
polyp opylenimine dend iplex
siRNA.
2G-(SNMe3I)11-FITC.
Neu ological
diso de s
Lac o e in. [60,61]
Sel -assembled
pa icle
Ca ionic micelles assembled om i amin E
succina e g a ed
ε
-polylysine polyme s
TRAIL plasmids (pDNA) Gliomas Apolipop o ein E (ApoE). [62]
Glucosyla ed-polyion complex polyme ic
micelle
An isense oligonucleo ide (ASO) Cen al ne ous
sys em (CNS)
diso de s
Glucose coa ing (GLUT-1-
media ed anspo s a egy).
[63]
Chime ic polyme somes siRNA Glioblas oma Ang2. [64]
Chime ic polyme somes Sapo in Glioblas oma (ApoE) pep ide. [65]
O he polyme ic
ca ie s
Chi osan-PMMA-PAA NPs Topoisome ase I inhibi o SN-38 B ain umo s Re oenan io pep ide shu le H-
pw pswmpp h -NH2.
[66]
Chi osan NPs G een Fluo escen P o ein
(GFP)- agged plasmid in
HEK293–293
B ain cance - [67]
Hyalu ona e Nanopa icles Neu oglobin S oke - [68]
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
20
inju y, in ec ion, and in lamma ion o main aining CNS homeos asis
[76]. These highly complex, dynamic, and selec i e ea u es o he BBB
a e o u mos impo ance o he co ec homeos asis o he CNS. Un-
de s anding he ole o BBB anspo e s o main aining homeos asis is
e y c ucial, since hey go e n he ansloca ion o a ious molecula
en i ies ac oss he BBB (Fig. 2a).
2.2. Blood-b ain ba ie dis up ion unde pa hological condi ions
The BBB unde goes dis inc i e changes in a ious neu ological dis-
o de s and diseases [70,71,77,78]. The pa hology o BBB in ol es
s uc u al, molecula , and unc ional modi ica ions o BBB cons i uen s,
ha impac he o e all physiological in eg i y and unc ion o he ba -
ie . E en hough he p ime cause o di e en diseases impac ing BBB
di e s, he p ima y ocus o BBB pa hology cen e s on i s pe meabili y.
In no mal condi ions, BBB is selec i ely pe meable (Fig. 2b), bu mos o
hese diso de s esul in inc eased pe meabili y due o al e a ions o
endo helial cells (sh inkage), loss o TJs p o eins, augmen ed anspo
o molecules ( anscy osis), and al e a ion in anspo (pa acellula and
anscellula ) sys ems [69,78]. Addi ionally, BBB b eakdown is e iden
by he loss o basemen memb ane, enhanced leucocy e ac i i y, de e-
io a ion o pe icy es esul ing in impai men o ascula ne wo k, and
de ached as ocy es, as desc ibed in Fig. 2c [71,76]. The o he hallma k
o BBB pa hogenesis is he elease o in lamma o y media o s such as
in e leukin (IL)-1β, in e e on (IFN)-γ, umou nec osis ac o (TNF)-
α
,
oxida i e compounds (e.g., NO, H
2
O
2
), lipid media o s (p os aglandin
E2 and F2a), asogenic agen s (e.g., his amine), and enzymes (e.g.,
ma ix me allop o einases) by bo h local and in il a ing immune cells
[77,78].
2.3. S a egies o blood-b ain ba ie c ossing
2.3.1. Physical and chemical dis up ion o he blood-b ain ba ie
Ex e nal s imuli-media ed me hods ha can egula e BBB pe me-
abili y o deli e y o he apeu ic agen s ha e been widely explo ed, and
hey showed high e ec i eness. They in ol e physical and biochemical
app oaches (Fig. 3).
Physical dis up ion: Ex e nal physical app oaches, like ocused ul a-
sound, magne ic esonance imaging, high pulse elec ic ields, lase s,
and elec o acupunc u e, ha e been used o p omo e he pe meabili y o
he BBB and he ollowing deli e y o he apeu ic agen s and (bio)
mac omolecules in he b ain issue [69,79–82]. Focused ul asound,
along wi h mic obubbles (gas- illed), in ol es high- equency sound
wa es ha a e p ecisely a ge ed o a speci ic a ea wi hin he b ain o
igge mic obubbles in he blood o ca i a ion [77]. This mechanical
in e ac ion esul s in empo a y and e e sible dis up ion o he BBB,
allowing he deli e y o he apeu ic agen s in CNS. The e ha e been
ecen ad ancemen s in using his app oach, some o which a e unde -
going clinical ials [83]. Addi ionally, ocused ul asound has been
coupled wi h magne ic esonance imaging and mic obubbles o p ecise
a ge ing o d ugs [78,80,83]. Low- and high-pulsed elec ical ields
ha e also been used o anspo small molecules by dis up ing he TJs o
he BBB [81]. Recen ly, lase s imula ion has been explo ed o modu-
la ing BBB pe meabili y. Fo his, plasmonic gold nanopa icles (AuNPs)
we e conjuga ed wi h an ibody BV11 (AuNPBV11) o a ge ing junc-
ional adhesion molecule A (JAM-A) and we e injec ed o mice
Fig. 2. (A) Schema ic ep esen a ion o a ious anscy osis pa hways o blood-b ain ba ie (BBB) ha egula es he anspo a ion o di e en molecules, bio-
mac omolecules and ions. Small lipophilic molecules passi ely di use h ough BBB ia anscellula lipophilic pa hway whe eas hyd ophilic molecules pass ia a
pa acellula pa hway. Essen ial nu ien s and ions along wi h glucose, i amins, elec oly es, amino acids, and nucleosides c oss he BBB h ough ca ie media ed
anscy osis (CMT) ia glucose anspo e iso o m 1 (GLUT-1) and la ge neu al amino acid anspo e 1 (LAT1). La ge biomac omolecules like p o eins, lipo-
p o eins, o pep ides, c oss he BBB h ough anscy osis mechanisms ia in e ac ion wi h speci ic ecep o s and is known as ecep o media ed anscy osis (RMT).
This in ol es ans e in ecep o (T R), insulin ecep o (IR), lipop o ein ecep o s, and lac o e in (L ) ecep o . Adso p i e media ed anscy osis (AMT) allows
anscy osis o la ge biomac omolecules (e.g., pep ides) and is based on elec os a ic in e ac ions be ween he posi i ely-cha ged subs a es and he nega i ely-
cha ged plasma memb ane. (B) Schema ic ep esen a ion o ans e se sec ion o BBB wi h i s componen s and unc ion du ing heal hy s a e, and (C) a e BBB
b eakdown. Bio ende has been used o c ea ing he desc ip i e image.
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
21

in a enously. One-hou pos -adminis a ion, 532 nm picosecond lase
was applied ansc anially, leading o ac i a ion o AuNPBV11. This
esul ed in he enhancemen o BBB pe meabili y, acili a ing he de-
li e y o immunoglobulins, adeno-associa ed i al ec o s, and lipo-
somes [82]. The e ec o i adia ion on he b ain is in ica ely associa ed
wi h powe and i adia ion ime, along wi h he dis ance be ween he
sou ce and he a ge ed a ea. No ably, nea in a ed ligh wa eleng h in
he ange om 700 o 1600 nm has ga ne ed p o ound in e es due o i s
abili y o pene a e deep issues and has been used o egula e BBB
pe meabili y. Recen s udies ha e applied nea in a ed i adia ion o
imp o e he abili y o ligh -sensi i e d ug deli e y sys ems wi h pho-
o he mal e ec s o pene a e BBB, o e ec i e ea men o dep ession
[69]. The use o elec oacupunc u e o imp o ing he pe meabili y o
BBB has also gained in e es . One o he s udies highligh s he
augmen a ion o BBB pe meabili y h ough he applica ion o elec o-
acupunc u e a ge ing he GV20 and GV26 acupoin s in a models [69].
Chemical dis up ion: The mos commonly used chemical eagen s o
dis up he in eg i y o he BBB, oge he wi h hei wo king condi ions,
applica ions, ad an ages and disad an ages a e summa ized in Table 3.
[69,77,78,80,84–92] Some o he pha maceu ical biological compounds
like zonula occludens oxins, Ce epo (a syn he ic pep ide analog o
b adykinin), LipoB idge (a nonimmunogenic o mula ion con aining
sho -chain oligoglyce olipids), ascula endo helial g ow h ac o
(VEGF), and chemical compounds such as oleic acid, lysophospha idic
acid, cyclodex ins, and sodium dodecyl sul a e a e also in ol ed in
ansien opening o he BBB [77,78,86].
The i uses also se e as s imula ing biological agen s ha help in
he opening o TJs by up egula ing chemokines. As example, s udies on
human b ain mic o ascula endo helial cells highligh ed he in ol e-
men o he human immunode iciency i us (HIV) ype 1 gp 120 i us in
enhancing BBB pe meabili y by deg ading TJs [78]. Addi ionally,
adeno-associa ed i us and Wes Nile i us also exhibi ed p omising
abili y o a ge CNS, wi hou dis up ing he BBB [78,95].
2.3.2. In asi e s a egies
Di ec injec ion/implan a ion: Di ec injec ions in ol e localized de-
li e y o he apeu ics o hei sus ained elease ia implan s in o he
b ain. This is used o ea condi ions such as cance s, s oke, neu o-
logical and men al diso de s [96]. Su gically placed implan s can p o-
ide sus ained elease o d ugs by opening he skull. The
ca mus ine-loaded biodeg adable implan s (Gliadel® wa e ), app o ed
by he Food and D ug Adminis a ion (FDA), placed du ing umou
esec ion, ha e shown imp o ed su i al a es in pa ien s acing GBM.
Also, nica dipine- eleasing solid implan s ha e been success ully used o
p e en neu ological diso de s ollowing s okes [96]. A he same ime,
long- e m (5 mon hs) deli e y sys ems ha e been explo ed o schizo-
ph enia o add ess ea men adhe ence issues associa ed wi h men al
diso de s [96].
In ace eb o en icula adminis a ion: In his app oach, he he a-
peu ics a e deli e ed in o he ce eb ospinal luid, speci ically in he
la e al en icle sys em o he b ain, ia an ou le ca he e o in a-
ce eb o en icula po implan ed unde he scalp o by pump [77,88].
Ou o his, he use o pumps is mo e p e alen , as i main ains con in-
uous and ele a ed d ug concen a ions in ce eb ospinal luid [77].
In ace eb o en icula implan s ha e been used o deli e chemo he -
apeu ics o b ain cance , opioids o pain managemen , and d ugs o
he ea men o neu ological diso de s like lysosomal s o age diso de s
(LSD), mucopolysaccha idosis, and o diso de s associa ed wi h ce e-
b al palsy (e.g., baclo en) [90]. Addi ionally, clinical ials a e going on
o amyo ophic la e al scle osis (ALS) and PD by adminis e ing VEGF
and pla ele -de i ed g ow h ac o s, espec i ely [88,90].
In a hecal adminis a ion: He e, he he apeu ics a e di ec ly injec ed
in o he space su ounding he spinal co d by lumba punc u e and a e
deli e ed o CNS pa enchyma ia ce eb ospinal luid. This app oach has
been app o ed o he deli e y o an isense oligonucleo ide o he
ea men o spinal muscula a ophy. Clinical ials a e going on o ALS
and HD [77,90].
2.3.3. Non-in asi e s a egies
Non-in asi e s a egies o he deli e y o he apeu ics ely on
pha macological app oaches ha exploi he endogenous anspo
mechanisms o enhanced BBB pe meabili y. These s a egies, ha
include chemical modi ica ion o he he apeu ic d ugs, anspo ca -
ie s, chime ic pep ides, nanoca ie s, T ojan ho se, e c., ha e
Fig. 3. Schema ic ep esen a ion o he mos common s a egies o blood-b ain ba ie (BBB) c ossing. Physical/chemical dis up ion includes ansien opening o
he BBB o acili a e he deli e y o he apeu ics. In asi e s a egies in ol e di ec implan a ion/injec ion o he apeu ics ei he di ec ly in he b ain o h ough he
ce eb ospinal luid (CSF). Non-in asi e s a egies equi e he use o ca ie s capable o deli e ing he apeu ics ac oss he BBB. Bio ende has been used o c ea ing
he desc ip i e image.
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Ac a Bioma e ialia 196 (2025) 17–49
22
Table 3
Summa y o a ious chemical eagen s used o BBB dis up ion.
Agen s Examples Mechanism Wo king Condi ion Applica ion Ad an ages/Disad an ages
Hype osmo ic
Agen s
Manni ol [77,78,80,
84,87–89]
Osmo ic p essu e g adien c ea ed,
which leads o sh inkage o
endo helial cells and dis up ion o
igh junc ion, and esul ing in
empo a y opening o he blood-
b ain ba ie (BBB)
A e ial Injec ion/in usion
(25%)
D ug Deli e y,
(chemo he apeu ics,
imaging agen s)
Ad an ages: Clinically
app o ed, enhanced
pe meabili y, non-in asi e,
apid ac i i y, b oad ange o
agen s, cos e ec i e
Disad an ages: Non selec i e,
inconsis en ba ie dis up ion,
neu ological oxici y
Glyce ol [80,85]Neu ological S udy, d ug
deli e y
Ad an ages: A ailabili y, low
cos
Disad an ages: Lowe
e icacy, Immunogenic isks
A abinose [77,78,80,
87,89,93]
In a enous adminis a ion D ug Deli e y Ad an ages: Biodeg adable,
e ec i e a low concen a ion,
used o hyd ophilic and
lipophilic d ugs
Disad an ages: Limi ed
in o ma ion,
isk o me abolic imbalances
Saline [89,90,93] In a enous adminis a ion
(23.4%)
Used in p eclinical models
o d ug deli e y and
con as agen s o CNS
Ad an ages: Cos e ec i e,
a ailabili y, easy
adminis a ion
Disad an age: Edema, issue
damage, hype na emia (high
sodium le els)
U ea [85,89,90,93]Used in p eclinical s udies
o d ug deli e y
Ad an ages: Cos e ec i e,
dis up s BBB a con olled
doses
Disad an ages: Sho li ed
dis up ion, elec oly e
imbalance
F uc ose [85] In a enous adminis a ion Used in p eclinical s udies
o d ug deli e y and
con as agen s
Ad an ages: Less oxic,
biocompa ible
Disad an ages: Limi ed
In o ma ion, me abolic
imbalances
Vasoac i e
Compounds
His amine [77,80,89,
90]
Binds wi h B2 ecep o s o
endo helial cells leading o
dis up ion o igh junc ion and
enhanced d ug pe meabili y
In a enous (10 o 100 µM) Used in p eclinical models
o d ug deli e y
Ad an ages: Minimal oxici y
Disad an ages: sho du a ion
o ac ion, non-speci ic
B adykinine [77,80,
87,88,88,90]
In a enous o
in ace eb al
adminis a ion
D ug deli e y (enhanced
deli e y o
chemo he apeu ics, small
molecules)
Ad an ages: Selec i e,
minimal oxici y
Disad an age: Sho du a ion
o ac ion, limi ed e icacy o
la ge molecules, cos
RMP-7 (analogues o
b andykinin [88,89]
Ad an ages: Mo e po en and
speci ic o B2 ecep o s han
b adykinin, highe hal -li e as
esis an o deg ada ion
Alkylglyce ols (e.g., 1-
O-pen ylglyce ol [80,
88,89]
In aca o id injec ion (200
mM)
D ug Deli e y
(Chemo he apeu ics)
Ad an ages: Re e sible,
inc ease in BBB pe meabili y
Disad an ages: Limi ed
e ec i eness, side e ec s
Leuco ienes (e.g.,
cys einyl leuko ienes)
[88,89]
Binds o he G-p o ein coupled
ecep o s CysLTR1 and CysLTR2,
igge ing he con ac ion o
endo helial cells and dis up ing igh
junc ion esul ing in enhanced
pe meabili y
In ace eb o e–n icula
injec ion (6pmol)
D ug Deli e y Ad an ages: Immune esponse
acili a ion
Disad an ages: Tissue
damage, long e m oxici y
Tumo nec osis ac o
A (TNF-A)/in e e on
c (INF-c) [94]
Tigh junc ion p o eins a e al e ed
ia in lamma o y cy okines
Sys emic o local
adminis a ion
D ug Deli e y,
neu oin lamma ion and
CNS esea ch
Ad an ages: Ta ge speci ic,
mechanis ic insigh s
Disad an ages: Sys emic side
e ec s, isk o
neu oin lamma ion
Chemical
compounds
Oleic Acid [77,78] I changes p o ein kinase C-induced
p o ein phospho yla ion, esul ing in
e e sible opening o BBB
In aca o id in usion Used in p eclinical s udies
o d ug deli e y
Ad an ages: Mild and
e e sible e ec
Disad an ages: Low
speci ici y, limi ed in o ma ion
Lysophospha idic acid
[77,78]
In a enous Injec ion Ad an ages: Re e sible e ec
Disad an ages: Limi ed
in o ma ion, isk o
neu oin lamma ion
Sodium lau yl
sulpha e [77,78]
Dis up s endo helial cell memb ane
by al e ing lipid bilaye
Di ec In usion on BBB D ug Deli e y and BBB
s udies
Ad an ages: Cos , Dose
dependen
(con inued on nex page)
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Ac a Bioma e ialia 196 (2025) 17–49
23
demons a ed p omising esul s wi h minimal ad e se e ec s. This e-
iew ocusses on he T ojan ho se app oach, and highligh s hei mode
o ac ion and he po en ial applica ion in he deli e y o bio-
mac omolecules ac oss he BBB.
Molecula T ojan ho ses a e designed o deli e he apeu ic mole-
cules (e.g., small-molecule d ugs, ecombinan p o eins, and genes)
ac oss he BBB by mimicking na u al biological p ocesses and s uc u es.
This s a egy in ol es non-in asi e app oaches, using an ibodies, pep-
ides, cells, and nanopa icles as T ojan ho ses, a ge ing endogenous
BBB ecep o s such as ecep o -media ed anscy osis (RMT) and
adso p i e-media ed anscy osis (AMT) o anscy osis o he apeu ic
biomac omolecules [97–99]. Examples o some o he T ojan ho se ap-
p oaches o BBB pene a ion a e desc ibed below (Fig. 3).
An ibody T ojan ho ses: This echnique uses gene ic enginee ing o
he apeu ics (neu o ophins, he apeu ic an ibodies, enzymes and decoy
ecep o s) wi h monoclonal an ibodies (mAb) (IgG domain) ha ing
speci ici y owa ds ans e in ecep o (T R) and human insulin e-
cep o (HIR) o gi e T RmAb and HIRmAb. These ac as a T ojan ho se
o deli e y o a ached d ugs ia RMT [100,101]. Fo example, T ojan
ho se Pabina usp al a, enginee ed by usion o idu ona e 2-sul a ase
(lysosomal enzyme) and hea y chain o T RmAb, has been used o
he Hun e synd ome and ecei ed ma ke app o al o he ea men o
b ain diso de s in Japan [100,102].
Pep ide T ojan ho ses: Angiopep-2 pep ide (Ang2) is a low-densi y
lipop o ein ecep o (LPR1)- a ge ing pep ide, ha enhances he BBB
pene a ion o an i-human epide mal g ow h ac o -2 mAb [103].
Simila ly, a no el de i a i e o pacli axel wi h Ang2 (ANG1005)
e ealed imp o ed d ug up ake in gliomas and is unde clinical ial [99,
104]. TAT is a posi i ely-cha ged cell pene a ing pep ide (CPP) de i ed
om he ansac i a o o ansc ip ion p o ein o he HIV. I has been
ound ha many ca ionic pep ides a e aken up by he cells h ough AMT
in i o. Howe e , poo b ain pe meabili y was obse ed in i o [98,
103]. Con a ily, ano he CPP, SynB pep ides, de i ed om a na u al
mammalian an imic obial pep ide, ha e shown be e deli e y o pola
biomolecules such as mo phine-6-glucu onide o he b ain in a clinical
ial, bo h in i o and in i o [78]. Addi ionally, SynB3 conjuga ed wi h
a ious low b ain-pene a ing chemo he apeu ic d ugs like doxo ubicin,
benzylpenicillin, pacli axel, and dala gin has demons a ed signi ican
b ain pene a ion and can be a po en ial s a egy o b ain cance
ea men [78].
Func ionaliza ion o nanopa icles: The apies based on app o ed
nanoca ie s (e.g., liposomes and polyme ic nanopa icles) and associ-
a ed echnologies (in asi e and non-in asi e) a e cu en ly being
in es iga ed o ea CNS diseases [99]. In his con ex , liposomes wi h
high biocompa ibili y, biodeg adabili y, and in insic compe ence o
BBB ha e been ex ensi ely explo ed as T ojan ho ses. Liposomes unc-
ionalised wi h polye hylene glycol (PEG) and biomolecules (T and
insulin) ha e been used o he deli e y o DNA encoding lysosomal
enzyme o he b ain o he ea men o mucopolysaccha idosis [105].
PEGyla ed liposomes u he unc ionalised wi h glu a hione (GSH) o
a ge ing GSH anspo e s o deli e y o doxo ubicin, me hylp ednis-
olone, and iba i in a e in p eclinical s udies [99]. Fo example,
PEGyla ed doxo ubicin-loaded liposomes a ge ing GSH anspo e s
ha e shown posi i e ou comes in e ms o an i umou ac i i y, and ha e
eached phase I/II clinical ials. The ea men was ound o be sa e and
well- ole a ed [105]. Simila ly, ea men wi h GSH PEGyla ed lipo-
somal me hylp ednisolone o phase I ials on 42 pa ien s, was deemed
sa e and well ole a ed a he apeu ic doses o MS [105]. In he case o
in a enous adminis a ion o iba i in encapsula ed GSH PEGyla ed
liposome, a ou old inc emen o he d ug in b ain mic odialysa es was
obse ed [99]. Two o he liposome-based T ojan ho se sys ems, SGT-53
(wi h T Ab and plasmid p53), and doxo ubicin-loaded PEGyla ed li-
posomes wi h ce uximab a e in phase I and phase II clinical ials o
GBM [105].
Cellula ca ie s: Inno a i e pa adigms, whe ein he immune cells
(monocy es, neu ophils, and mac ophages) a e ha nessed o BBB
he apeu ic in e en ions, ha e gained in e es in ecen imes. In his
app oach, cells a e used as T ojan ho ses. Cells a e ei he gene ically
modi ied o p oduce he apeu ically ac i e pep ides and RNA mole-
cules/p o eins o can ca y he apeu ics a ge ing BBB [99]. Immune
cells ha e inhe en p ope ies o ansmig a e ac oss BBB by changing
hei shape (diapedesis) and ha e been used o b ain deli e y in dis-
eases in ol ing in lamma ion. Enginee ed mac ophages exp essing glial
cell line-de i ed neu o ophic ac o (GDNF) in a PD model demon-
s a ed long- e m neu op o ec i e e ec s a he onse o disease p o-
g ession and educed b ain in lamma ion [99]. Fu he , neu al
p ecu so s em cells and hema opoie ic s em cells can also in e ac wi h
BBB cells unde in lamma ion. In ecen s udies, neu al p ecu so s em
cells and hema opoie ic s em cells we e enginee ed o exp ess he
an i umou biomolecule umou -selec i e p oapop o ic dea h ecep o
ligand (TRAIL), esul ing in ea ing me as a ic b ain umou [99]. In
ano he se o cell-media ed d ug deli e y examples, magne ic lipo-
somes loaded wi h he d ug diclo enac and unc ionalised wi h he
pep ide mo i RGD (a ginylglycylaspa ic acid) we e able o a ge
monocy es and neu ophils in an IL-1β induced b ain in lamma ion a
model. In ha s udy, RGD ac ed as a a ge ing ligand o in eg in
Table 3 (con inued)
Agen s Examples Mechanism Wo king Condi ion Applica ion Ad an ages/Disad an ages
Disad an ages: Nonspeci ic,
Side e ec s
Sodium dodecyl
sul a e [77,78]
In e ac s wi h lipid and p o ein o
cell memb ane
  Ad an ages: Dose dependen ,
e e sible
Sodium cap a e (C10)
[89,91]
In eg a es in o he lipid bilaye o
endo helial cells which inc eases
memb ane luidi y and loosening he
igh junc ion a o ing pa acellula
anspo s
In aca o id adminis a ion
(5–25 mM)
D ug Deli e y Ad an ages: Re e sible,
e ec i e o bo h small and
la ge molecules
Disad an ages: Limi ed
in o ma ion, non-selec i e,
in lamma ion
Cyclodex ins [78] BBB dis up ion by ex ac ing
choles e ols om endo helial cells
In a enous (1mM-10 mM) D ug Deli e y
(hyd ophobic d ugs)
Ad an ages: Biodeg adable,
selec i e ac ion on cell
memb ane
Disad an ages: Limi ed
e icacy o hyd ophilic d ugs,
side e ec s
A oma ic
subs ances
Bo neol [84] Re e sibly disassembles he igh
junc ion p o eins (claudins and
occludins), ansien ly dis up ing he
BBB in eg i y
D ug Deli e y,
neu op o ec ion
Ad an ages: Re e sible e ec ,
na u al o igin, b oad
applicabili y
Disad an ages: Concen a ion
dependen oxici y,
nonspeci ic, limi ed ac i i y
E. Rome o-Ben e al.
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24
ecep o s exp essed on monocy es and neu ophils, which enhanced he
up ake o diclo enac-loaded liposomes by he cells. As a esul , i was
obse ed 9.1 old inc emen o d ug eaching he b ain. Table 4 sum-
ma izes he di e en s a egies o BBB c ossing desc ibed in his sec ion,
highligh ing he ad an ages and disad an ages o each app oach [69,77,
84,87,88,90,93,94,106–109].
Among he s a egies explained abo e, we will conside he ein he
use o polyme ic nanoca ie s o deli e he apeu ic biomac omolecules
(e.g., enzymes, g ow h ac o s, genes) ac oss he BBB om he blood-
s eam. The molecula s uc u e o polyme s can be inely adjus ed
du ing he syn he ic app oach o ia pos -polyme iza ion app oaches,
esul ing in polyme ic nanoca ie s wi h uneable mechanical, physi-
cochemical, and su ace p ope ies. The wide a ie y o a ailable poly-
me s (e.g., syn he ic s. na u al, biodeg adable s. non-biodeg adable,
s imulus- esponsi e) allows he ab ica ion o a ple ho a o nano-
o mula ions ha ha e shown p omising esul s ega ding he p o ec-
ion o sensi i e biomac omolecules om ex e nal condi ions (e.g.,
p esence o p o einases, changes in pH and ionic s eng h) and BBB
c ossing.
3. Polyme -based nanoca ie s o c oss he blood-b ain ba ie
In he p esen e iew, he a ious polyme ic nanoca ie s a e o ga-
nized acco ding o hei a chi ec u e, which ul ima ely dic a es hei
physicochemical p ope ies and unc ionali y. In his con ex , biode-
g adable solid nanopa icles a e no able o hei compac ness, hyd o-
phobici y, and unable biodeg adabili y; nanogels a e dis inguished by
hei so , h ee-dimensional s uc u e and en i onmen al adap abili y;
dend ime s a e ecognized o hei well-de ined, monodispe se, highly
b anched, and symme ical a chi ec u e; and sel -assembled nano-
pa icles/nanocapsules a e cha ac e ized by hei e sa ili y in e ms o
syn he ic app oaches, enabling he encapsula ion o sensi i e
biomac omolecules.
3.1. Biodeg adable solid nanopa icles
Biodeg adable solid nanopa icles a e mainly o mula ed by using
alipha ic polyes e s. In his con ex , biocompa ible and biodeg adable
nanopa icles based on FDA-app o ed poly(
ε
-cap olac one) (PCL), poly
(lac ide) (PLA), and i s copolyme s wi h glycolide (PLGA) ha e ecei ed
pa icula a en ion as ma e ials o he ab ica ion o b ain- a ge ed
d ug deli e y sys ems. A wide a ie y o ca gos, mainly based on
small MW d ugs, ha e been success ully encapsula ed in o hese
nanopa icles o add ess neu odegene a i e diseases such as AD, PD, and
o he diseases and diso de s o he CNS [110]. Mo eo e , hese nano-
pa icles ha e been p o ed o be p omising nanoca ie s o deli e (bio)
mac omolecules ac oss he BBB. Hence, hey a e pos ula ed as po en ial
en i ies o enzyme eplacemen he apies (ERT) [48], small in e e ing
RNA (siRNA) he apies [49,51], b ain-de i ed neu o opic ac o he -
apies (BDNF) [111] and i amin D-binding p o ein (DBP) [50] o LSDs,
GBM, o TBI, among o he s.
As (bio)mac omolecule nanoca ie s, PCL, PLA, and PLGA nano-
pa icles p esen ce ain ad an ages o e o he deli e y sys ems. They
a e comme cially a ailable, easy o manu ac u e, and o e e sa ile
nanopa icle o mula ions wi h adjus ed physical, chemical, and me-
chanical p ope ies. The MW, as well as he co-monome cons i uen s
and a io, di ec ly a ec he iscosi y, solubili y, glass ansi ion em-
pe a u e (T
g
), c ys allini y deg ee, and phase beha io o he polyme
[112,113]. Amo phous ma ices acili a e a mo e uni o m dis ibu ion o
he ac i e/ he apeu ic compounds and endow he polyme wi h highe
deg ada ion a es. In his sense, he PLA componen (i.e., lac ide) plays
an impo an ole. The c ys alline phase can be supp essed by modi ying
he s e eochemis y o lac ide: while s e eo egula PLA (pu e D- o
L-lac ide) is c ys allizable, he s e eo-i egula PLA (D,L-lac ide) is
amo phous [114]. The e o e, (co)polyme s based on D,L-lac ide, such as
poly(D,L-lac ide) (PDLLA), poly(D,L-lac ide-co-
ε
-cap olac one)
(PDLCL), and poly(D,L-lac ide-co-glycolide) PDLLGA (usually epo ed
in bibliog aphy and comme cialized as PLGA) a e he mos sui able
candida es o his d ug deli e y applica ions. Among hese polyme s,
PLGAs a e he mos epo ed and used as s anda d nanopa icles. In
gene al, he biodeg ada ion kine ics o hese nanopa icles, which is
essen ial o ca go elease, is easily p edic ed by adjus ing he MW and
he composi ion o he copolyme s. The inc ease in MW and D,L-lac ide
uni s gene ally educes he biodeg ada ion a e in PLGA copolyme s.
This ea u e allows he design o nanopa icles wi h con olled and
ailo able elease p o iles o ac i e agen s anging om mon hs o yea s
o deg ada ion imes. Mo eo e , MW and he co-monome a io play an
impo an ole in uning nanopa icle elas ici y. This pa ame e has been
epo ed o be an impo an condi ion o con ol he biological in-
e ac ions o nanopa icles wi h he b ain endo helium, he eby ha ing a
di ec impac on hei anspo ac oss he BBB. In his sense, high MW
and lac ide- ich polyme s will exhibi highe s i ness, which acco ding
o epo ed s udies, migh p omo e highe associa ion wi h endo helial
cells and anspo h ough hem [115,116].
The ab ica ion echnique is essen ial o design speci ic nanopa icles
wi h he abili y o ca y hyd ophilic (bio)mac omolecules o he b ain
Table 4
Compa a i e analysis o di e en s a egies o BBB c ossing, highligh ing he ad an ages and disad an ages o each s a egy.
S a egies Examples Ad an ages Disad an ages
Physical
Dis up ion
Focused Ul asound (FUS) [77,84,87,88,
93]
P ecise a ge ing, non-in asi e, empo a y opening,
con olled and adjus able pa ame e s.
Tissue damage, equi emen o high-end equipmen ,
ope a ional expe ise, cos .
High Pulse Elec ic Field [94] Pe meabili y h ough elec opo a ion, e e sible. Cellula damage, p ecise deli e y, limi ed esea ch.
Lase s and Elec opunc u e [69,94] Non-in asi e, adjus able pa ame e s. Cellula damage, side e ec s, limi ed clinical da a,
echnical challenges.
Chemical
Dis up ion
Hype osmo ic Agen s [84,90] Clinically app o ed, enhanced pe meabili y, non-
in asi e, apid ac i i y, b oad ange o agen s, cos
e ec i e.
Non- a ge ing, cellula damage, ansien and
inconsis en he apeu ic e ec , sys emic oxici y,
egula o y and sa e y conce n.
In asi e
S a egies
Di ec Injec ion/Implan a ion [84,88,90,
106]
Localized deli e y, ci cum en ing BBB, highe d ug
concen a ion, educed sys emic oxici y.
In asi e, limi ed d ug dis ibu ion, ad e se local
eac ions, echnical complexi y, cos .
In ace eb o en icula and In a hecal
Adminis a ion [77,88,90,93,106,109]
Di ec CNS deli e y, ci cum en ing BBB, uni o m
d ug dis ibu ion wi h enhanced he apeu ic
e iciency.
In asi e, p ocedu e ela ed complica ions, echnical
complexi y, side e ec s.
Non-In asi e
S a egies
An ibody and Pep ide T ojan Ho se [103,
108,109]
Ta ge ed deli e y, high selec i i y and speci ici y,
educed sys emic oxici y, high anscy osis,
e sa ili y in payload.
Complex enginee ing and op imiza ion, immune
esponse, a iable BBB pene a ion, p oduc ion and
scalabili y, s abili y issue, cos .
Func ionaliza ion o Nanopa icles [69,77,
88,90,107,109]
Ta ge ed deli e y, speci ici y, imp o ed pene a ion,
con ol-led elease, e sa ili y, mul i unc ional.
Ba ch o ba ch a iabili y, oxici y and clea ance, s abili y
issues.
Cellula Ca ie s [77,88,90,107,109] Ta ge ed deli e y, educed immunogenici y,
biodeg adable, mul i unc ional, e sa ili y, e icien
gene deli e y.
Pa hogenici y, s abili y, cul u ing and main enance,
scalabili y, limi ed payload, egula o y and e hical issues.
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25
3.4. Sel -assembled polyme ic nanopa icles
Inspi ed by biology and combining sup amolecula chemis y wi h
nano echnology, sel -assembled nanoca ie s can be p oduced h ough
spon aneous in e ac ion o molecules o o m o ganized s uc u es
[181–183]. The e a e a ious sel -assembled nanoca ie s ha ha e
been s udied o c oss he BBB, such as liposomes [62,184], niosomes
(using solu e ca ie anspo e s) [185], lipid nanoca ie s [186],
polyme ic micelles [187], polyme somes (polyme esicles) [188], and
laye -by-laye (LbL) capsules, among o he s. As he ocus o he p esen
e iew is on polyme -based nanoca ie s, he ein we elabo a e upon
h ee sel -assembled polyme ic nanoca ie s: polyme ic nanopa icles
based on amphiphilic block and g a copolyme s, polyme somes, and
LbL capsules.
Amphiphilic block and g a copolyme s ep esen a no able ca ego y
o polyme ic nanopa icles, ea u ing dis inc hyd ophilic and hyd o-
phobic polyme blocks chemically linked o c ea e s uc u es wi h
excep ional sel -assembly capabili ies. These blocks can ei he be
neu al polyme s (hyd ophilic o hyd ophobic) o polyelec oly es
(anionic, ca ionic, o zwi e ionic) [189–191]. In an aqueous en i on-
men , hese amphiphilic block copolyme s sel -assemble o o m poly-
me ic micelles abo e hei c i ical micelle concen a ion (CMC). Abo e
his concen a ion, he hyd ophobic inne co e o he copolyme comes
close o agg ega e and dis ances i sel om wa e molecules [192].
These a e gene ally made o biocompa ible, non-immunogenic, biode-
g adable blocks such as polyes e s, poly(p opylene oxide), o poly
(amino acids) linked o biologically compa ible co ona- o ming blocks
like PEG [193,194] and display a co e-shell nanos uc u e. In addi ion,
g a copolyme s p oduced by he hyd ophobiza ion o hyd ophilic
polyme ic backbones (e.g., polysaccha ides, polyols) can gi e place o
mo e complex nanos uc u es such as mul imicella sys ems ha enable
g ea e EE [195]. Thei ease o unc ionaliza ion makes hem an e icien
nanosys em o b ain a ge ing by bo h in a enous and in anasal
adminis a ion [196,197]. Howe e , depending on he adminis a ion
s a egy, nanoca ie ea u es such as size and su ace mus be p ope ly
enginee ed. Fo example, he g oup o Sosnik de eloped chi osan-based
sel -assembled nanoca ie s ha we e su ace-modi ied wi h shu le
pep ides and inc eased he deli e y o small-molecule an icance d ugs
o he CNS [66,198]. Thei in es iga ion in he CNS deli e y o (bio)
mac omolecules is cu en ly being in es iga ed. Va ious app oaches
used o he unc ionaliza ion o polyme micelles o b ain a ge ing a e
shown in (Fig. 8) [199]. Plu onic® block copolyme s, also known as
poloxame s, exempli y his phenomenon and ha e ga ne ed signi ican
in e es due o hei abili y o impede d ug e lux anspo e s, such as
he inhibi ion o P-gp exp essed on he BBB, hus enhancing d ug de-
li e y o he CNS [200,201]. Plu onic® a e poly(e hylene oxide)-poly
(p opylene oxide)-poly(e hylene oxide) (PEO-PPO-PEO) iblocks,
o ming an amphiphilic copolyme . The manipula ion o he numbe o
hyd ophilic EO and hyd ophobic PO uni s p o ides a e sa ile means o
ailo ing hese copolyme s o speci ic applica ions [200,202]. Wi h
o e 50 Plu onic® molecules comme cially a ailable om BASF Co p.
(Pa sippany, NJ, USA), each cha ac e ized by di e en
hyd ophilic-lipophilic balance (HLB) and CMC, hese copolyme s o e a
spec um o possibili ies o ailo ing pa icle size, d ug loading, s a-
bili y, and d ug elease p o iles in he pu sui o op imized he apeu ic
ou comes.
The classi ica ion o Plu onic® copolyme s in o ou ca ego ies based
on di e ences in HLB and hyd ophobic PPO chain leng h u he elu-
cida es hei di e si y [203]. The i s class includes hyd ophilic Plu -
onic® wi h an HLB o 20–29, such as F68, F108, and F127, whe e F
means ha he p oduc is supplied in he o m o lakes [190,204,205].
These no only exhibi good hyd ophilici y bu also boas excellen
biocompa ibili y [206], con ibu ing o d ug accumula ion and p o-
longed blood ci cula ion ime [207]. The second class comp ises
Fig. 8. Schema ic ep esen a ion o polyme ic micelles o d ug deli e y. The image illus a es mul i unc ional polyme ic micelles wi h a ious modi ica ions o
enhanced d ug deli e y. The co e is hyd ophobic, consis ing o polyme s like PCL (polycap olac one), PLA (polylac ic acid), and PPO (polyp opylene oxide), while
he co ona is hyd ophilic, o med by PEG (polye hylene glycol), PVP (poly inylpy olidone), o PEO (polye hylene oxide). Modi ica ions include co e c oss-linking
o s abili y, ligand a ge ing ecep o s (e.g., ans e in, ola e) o ecep o -media ed a ge ing, and s imuli- esponsi e elemen s o con olled d ug elease.
Addi ional ea u es such as luo opho es and imaging agen s allow in i o acking, cell-pene a ing pep ides enhance cellula up ake, and c oss-linked co onas
imp o e s uc u al in eg i y. Ap ame s a e used o speci ic a ge ing, and su ace cha ge modi ica ions op imize in e ac ions wi h biological memb anes. These
micelles encapsula e d ugs, siRNA, p o eins, and o he agen s o a ge ed and e icien he apeu ic deli e y. Adap ed wi h pe mission om [199]. Copy igh ©
2022 Else ie .
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Ac a Bioma e ialia 196 (2025) 17–49
32

Plu onic® wi h a lowe HLB and sho e PPO chain, ep esen ed by
liquid L64 [208], L44 [209], and L35 [210], which impa s nano-
s uc u es wi h he abili y o sel -assemble in aqueous media, o e ing a
mo e sui able size (10–100 nm) and s able s uc u e [211]. The hi d
class ea u es Plu onic® wi h a lowe HLB and a PPO chain leng h
anging om 30 o 60 and in pas e o m a oom empe a u e, including
P85 [212], P105 [213], and L61 [214], which exhibi dissolu ion and
sel -assembly p ope ies in wa e , making hem sui able o loading
hyd ophobic d ugs. Addi ionally, hese copolyme s consume adenosine
iphospha e (ATP) in mul id ug- esis an cance cells, inhibi ing P-gp
and p olonging d ug ci cula ion ime [215,216]. The ou h class o
Plu onic® wi h a lowe HLB and a PPO chain exceeding 60, ea u ing
P123 and L121, wi h he longes PO chain, is widely used o loading
d ugs due o i s g ea e hyd ophobici y [217,218].
The encapsula ion o (bio)mac omolecules wi hin sel -assembled
nanoca ie s is a challenge ha can be o e come by ha nessing he
ad an ages o sel -assembled nanopa icles and s a egically binding
biomac omolecules h ough en apmen , adso p ion, o co alen
a achmen , ans o ming hese copolyme s in o T ojan ho ses, acili-
a ing he enhanced anspo and deli e y o he apeu ic payloads o
he b ain. Ce ain amphiphilic nanopa icles modi ied wi h p o eins,
pep ides, RNA, and d ugs ha e shown he abili y o c oss he BBB. Fo
ins ance, Poly(β-L-malic acid- i leucine)-copolyme has been used o
anspo miRNA ac oss he BBB. This sys em u ilizes he LRP-1 ans-
cy osis pa hway and amyloid be a (Aβ) pa hway by conjuga ing a D-
con igu ed (D3)-pep ide as a ec o o speci ic a ge ing, achie ing
neu on-selec i e deli e y o miRNA in an AD mouse model [219].
Ano he no able example in ol es he use o Lep in-Plu onic® 85 (P85)
conjuga es. This amphiphilic copolyme a ge s he lep in anspo e
and has shown p omising esul s as an an i-obesi y d ug. I s bene i s
include enhanced pe iphe al bioa ailabili y, inc eased b ain up ake,
and he abili y o c oss he BBB independen ly o he lep in anspo e
[220]. Fu he mo e, he T R-T12-PEG-PLGA and TATH7-PEG-PLGA
sys ems u ilize T R o anspo he T R-T12 pep ide, TATH7 pep ide,
and pacli axel ac oss he BBB. The s a egy in ol es conjuga ion wi h
he T R-T12 and TATH7 pep ide shu le, and in i o pha macodynamic
e alua ion demons a ed a po en an i- umo e ec in subcu aneous and
no mo opic glioma models, signi ican ly ex ending he li e cycle o
umo -bea ing mice [221].
On he o he hand, while amphiphilic copolyme s can c oss he BBB,
speci ic a ge ing o desi ed b ain egions emains challenging. S a e-
gies like conjuga ion wi h b ain-speci ic ligands o an ibodies a e c ucial
o maximizing e icacy and minimizing o - a ge e ec s. E icien
encapsula ion and con olled elease o (bio)mac omolecules wi hin
amphiphilic copolyme s emain key challenges. Op imizing polyme
a ios, inco po a ing s imuli- esponsi e elease mechanisms, and
explo ing co-assembly wi h o he polyme s a e p omising s a egies.
Ex ensi e p eclinical and clinical s udies a e necessa y o es ablish
sa e y and e icacy o egula o y app o al. Despi e hese di icul ies,
amphiphilic copolyme s hold immense po en ial o anspo ing bio-
mac omolecules ac oss he BBB. Con inued esea ch e o s ocused on
add essing hese limi a ions and explo ing inno a i e design s a egies
can help o mo e close he echnology o ea ing a ious neu ological
diso de s.
Polyme somes a e syn he ic esicles composed o amphiphilic block
copolyme s, wi h a hyd ophobic bilaye memb ane and g ea e deg ee
o complexi y in compa ison o he a o emen ioned co e-shell polyme ic
micelles (Fig. 9a). Polyme somes a e usually ab ica ed using diblock,
iblock o mul iblock copolyme s by ollowing di e en me hods o
induce hei sel -assembly including sol en -swi ch (o mic o luidic
me hod), pH- uning, polyme ehyd a ion, polyion complex esicles
(PICsomes) ab ica ion app oach, a combina ion o sel -assembly/
polyme iza ion (i.e., polyme iza ion-induced sel -assembly), and
cen i uga ion me hod. A e hei sel -assembly, sonica ion, memb ane
ex usion, o al e na i e me hods can be used o pu i y and/o adjus
hei size [222]. Some ypical polyme s o p oduce polyme somes o
nanomedicine a e PEG [223], diblock copolyme s o dex an and PLGA
(DEX–PLGA), poly(bu adiene)(PBd)-PEG [224], and diblock copolyme s
o PEG and PCL [225,226]. Compa ed o liposomes, polyme somes ha e
a hicke bilaye s uc u e, which imp o es hei physical s abili y and
inc ease hei blood ci cula ion [224]. Con a ily o polyme ic micelles,
ha a e usually limi ed o he encapsula ion o hyd ophobic d ugs,
polyme somes can accommoda e bo h hyd ophilic and hyd ophobic
ca gos in hei s uc u e. Polyme somes ha e gained a en ion in cance
nanomedicine and d ug deli e y sys ems due o hei ad an ageous
p ope ies, such as g ea s abili y, e sa ili y in design, and unable ca-
pabili ies o e ec i e ca go encapsula ion and con olled elease o
an icance he apeu ics [222].
Rega ding he use o polyme somes o deli e he apeu ic agen s in
he b ain en i onmen , se e al a emp s ha e been desc ibed in li e a-
u e. Yu e al. unc ionalized he su ace o 100 nm PEG-PLGA poly-
me somes wi h lac o e in o c oss he BBB and imp o e he deli e y o
luo escen 6-couma in and S14G-humanin (a neu op o ec i e pep ide)
o he b ain issue. Pha macokine ic s udies ollowing in a enous in-
jec ion sugges ed ha 101 lac o e in ligands pe polyme some was he
op imized numbe o p omo e he pe meabili y o he polyme somes
ac oss he BBB and ensu e b ain- a ge ed deli e y [223]. Geo gie a e al.
p esen ed a o mula ion o PBd-b-PEG polyme somes, which we e
deco a ed wi h pep ide G23 o inc ease hei capaci y o a ge gangli-
oside GM1 o ca eolae-media ed endo helial anscy osis. P elimina y
in i o s udies o hese polyme somes in an endo helial T answell®
model showed ha he polyme somes we e capable o pene a ing he
BBB h ough e icien endo helial cells anscy osis [224]. In addi ion, in
i o biodis ibu ion s udies a e in a enous injec ion in mice showed
ha G23- unc ionalized polyme somes accumula e in he b ain pa en-
chyma [227]. This is an ad an age o G23- unc ionalized polyme somes
o e some epo ed T - a ge ed sys ems, which mainly accumula e in he
b ain capilla y and do no each o he pa enchyma egion.
Ac i e a ge ing s a egies enable he nanoca ie s o c oss he BBB
by means o an in e ac ion h ough he speci ic ligands and hey ha e
been applied o bo h polyme ic micelles and polyme somes, aiming o
imp o e he up ake o he nanoca ie s by endo helial cells. One ac i e
a ge ing s a egy is o a e se he nanoca ie s in he BBB using ca ie
p o eins, such as GLUT-1, which is speci ically and highly exp essed on
endo helial cells o he BBB. Su Min e al. de eloped glucosyl-poly
(e hylene glycol)-b-poly(L-lysine) modi ied wi h 3-me cap op opyl
amidine and 2- hiolaneimine (Glu-PEG-PLL(MPA/IM)) polyme ic mi-
celles. As explained be o e, polyme ic micelles a e also ob ained by sel -
assembly o amphiphilic polyme s [228]. These glucosyla ed-polyion
complex polyme ic micelles we e loaded wi h an isense oligonucleo-
ide (ASO) ha we e unc ionalized wi h di e en quan i ies o glucose
o s udy he e ec o he ligand densi y and he accumula ion o nano-
pa icles in b ain. A g oup o nanoca ie s ha was coa ed wi h 52
glucose ligands pe nanopa icle showed 17 imes highe accumula ion
in he b ain compa ed o he g oup wi hou glucose coa ing, indica ing
he g ea po en ial o GLUT-1-media ed anspo s a egy [63]. Shi
Yanan e al. disco e ed a new me hod o enhance he clinical use o RNAi
in glioblas oma he apy. This me hod in ol es he de elopmen o an
Ang2 pep ide-deco a ed chime ic polyme some (ANG-CP), which
e ec i ely packs and p o ec s an i-PLK1 siRNA (siPLK1). In i o s udies
indica e ha ANG-CP may e icien ly a e se he immo alized mouse
b ain endo helial cell line (bEnd.3) monolaye , acili a e he anspo o
siRNA in o he cy oplasm o U-87 MG glioma umo cells h ough he
LRP-1-media ed pa hway, and ma kedly silence PLK1 mRNA and i s
associa ed oncop o ein in U-87 MG cells [64]. In his way, Jiang Yu e al.
sugges using a chime ic polyme some (CP) deco a ed wi h ApoE
ins ead o Ang2 as a a ge ed p o ein he apy o ea ing glioblas oma.
This showed be e pene a ion h ough he bEnd.3 monolaye in in
i o BBB models [65].
Among sel -assembled polyme ic nanoca ie s, mul ilaye polyme
capsules ha e a ac ed inc easing a en ion in ecen yea s. Mul ilaye
polyme capsules a e usually ab ica ed ia he LbL app oach, which
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Ac a Bioma e ialia 196 (2025) 17–49
33
Fig. 9. (A) Schema ic illus a ion o polyme some s uc u es, which a e ob ained by sel -assembly o amphiphilic block copolyme s. (B) A schema ic illus a ion o
laye -by-laye (LbL) deposi ion o opposi ely cha ged polyelec oly es on a nega i e co e o sac i icial empla e. Final LbL nanopa icle wi h blood-b ain ba ie
(BBB)- a ge ed ex e nal laye o acili a e he passage o nanopa icles h ough he BBB and deli e i s ca go in o he b ain. Bio ende has been used o c ea ing he
desc ip i e image. (C) Up ake o LbL nanopa icles wi h h ee co es (lipo: liposomes, PLGA: poly (lac ic-co-glycolic acid), PS: ca boxyla ed polys y ene), which we e
deposi ed by one laye o poly-L-a ginine (PLR) polyca ion and inal laye o di e en polyanions (CMDex: ca boxyme hyldex an, HA: hyalu onic acid, PLD: polyL-
aspa ic acid, PLE: poly-L-glu amic acid, and PSialA: polysialic acid). The up ake by he monolaye s ha we e g own in T answell shows supe io i y o liposome co e
o e o he s i e co es. (D) Pe meabili y o he LbL nanopa icles wi h di e en co es bu wi h he same las laye o PLD in he mice BBB demons a es mo e
pe meabili y o LbL nanopa icles wi h liposomal co e. (E) BBB pe meabili y o ba e liposomes and liposome-based LbL nanopa icles wi h di e en su ace unc-
ionaliza ion in mice showed ha he pe meabili y o LbL nanopa icles wi h hyalu onic acid (HA) ex e nal laye ac oss mice BBB was he g ea es . Adap ed wi h
pe mission om [243]. Copy igh © 2023 John Wiley & Sons. Bio ende has been used o c ea ing he desc ip i e image.
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
34
elies on he al e na e deposi ion o opposi ely-cha ged polyme s on o a
empla e (Fig. 9b) [229]. The s epwise p ocess in he LbL app oach al-
lows he p ecise con ol o e he su ace p ope ies (i.e., cha ge and
unc ionali ies) and he size o he capsule [181,230]. LbL capsules ha e
been acco dingly conside ed as po en ial d ug deli e y and he anos ic
nanosys ems o a wide a ie y o biomedical applica ions [229,
231–233]. Beyond d ugs o small MW, LbL (nano)capsules ha e
demons a ed hei capaci y o deli e he apeu ic biomac omolecules,
such as genes and enzymes [234–237]. As an illus a ion o his e sa-
ili y and mul i- unc ionali y associa ed o LbL sys ems, Boehnke e al.
in oduced click chemis y in o LbL nanopa icles, which enables hem
o combine a biosensing pep ide and a a ge ing pep ide wi hin he same
ca ie . This mul i unc ional sys em demons a ed a sensi i e de ec ion
o h ee di e en ypes o cance s and simul aneous gene silencing as a
esul o success ul siRNA deli e y [232]. This s udy highligh s he po-
en ial o LbL nanopa icles o load high amoun s o a ious la ge bio-
mac omolecules, such as siRNA and pep ides, in a single o mula ion.
One o he impo an aspec s o a ge ed d ug deli e y o b ain
issue is ha nanopa icles a e no clea ed ou om he blood s eam ia
phagocy osis and he ecogni ion o immune sys em. The e a e some
s a egies ha ha e been implemen ed o a oid he up ake by mac o-
phages, such as cell hi chhiking, su ace modi ica ion o nanopa icles,
and he modula ion o he physiological en i onmen [238]. Łukasie-
wicz e al. de eloped 100 nm LbL nanocapsules loaded wi h clozapine
and unc ionalized wi h PEG o in es iga e hei po en ial o c oss he
BBB [239]. Resul s demons a ed ha he p oposed su ace modi ica ion
s a egy dec eased hei phagocy osis and up ake by mac ophages, bu
did no dec ease he endo helial cells up ake. Mo eo e , all he g oups
we e able o c oss he BBB in an in i o BBB T answell® model, and PEG
unc ionaliza ion imp o ed he anscy osis and educed he cy o ox-
ici y o clozapine-encapsula ed nanocapsules. In addi ion, hei inhibi-
ion s udies indica ed ha ca eolae-dependen anscy osis played a ole
in he in e naliza ion o nanocapsules by endo helial cells [239].
Ano he s a egy o BBB anspo elies on acili a ing anscy osis
in BBB endo helial cells h ough a mechanism media ed by low-densi y
lipop o ein ecep o - ela ed p o eins, such as LRP1 [188,240]. S aehla
e al. ab ica ed LbL nanocapsules using liposomes as a empla e and
p opa gyl-modi ied poly(L-aspa ic acid) as he ex e nal laye , which
was u he modi ied wi h Ang2 pep ide [241]. They used hese nano-
pa icles o cispla in deli e y in a mic o luidic BBB-GBM. In compa i-
son wi h ba e liposomes and non- unc ionalized LbL nanopa icles, he
LbL nanocapsules unc ionalized wi h Ang2 we e p e e en ially accu-
mula ed in mic o ascula ne wo k nea GBM sphe oids. Thus,
Ang2- unc ionalized LbL nanopa icles showed mo e e ec i eness in
GBM umo cell killing wi h espec o ba e liposomes and ee cispla in.
These ou comes demons a ed he supe io i y o Ang2- unc ionalized
nanopa icles, pene a ing he BBB by LRP1-media ed anscy osis.
This wo k also demons a ed he inc eased exp ession o LRP1 in he
ascula ne wo k in p esence o GBM sphe oids.
Addi ionally, he in insic mechanical p ope ies o he LbL pa i-
cles/capsules can also de e mine hei capaci y o c oss he BBB. I was
shown ha he s i ness and de o mabili y o LbL nanopa icles is mainly
dependen on he co e a he han on su ace unc ionali ies. Kong e al.
we e able o une he s i ness o LbL nanopa icles by al e ing he
choles e ol con en in liposome syn hesis, which was used as a co e. This
s udy epo s ha mo e de o mable, luid, and complian LbL nano-
pa icles we e ob ained by choles e ol addi ion o liposomal co e.
Compa ed o s i LbL nanopa icles, complian LbL ones can pene a e
il e memb anes (wi h 100 nm po e size) mo e easily, which could also
ha e be e BBB pene a ion [242]. In a simila s udy, Lamson e al.
ocused on he e ec o co e s i ness and su ace unc ionaliza ion o
LbL nanopa icles on hei anspo h ough he BBB. To his end, hey
in es iga ed h ee di e en nega i ely-cha ged co es, i.e., liposomes,
PLGA, and ca boxyla ed polys y ene, and modi ied he las laye o he
nanopa icles by using di e en polyanions such as ca boxyme hyldex-
an, hyalu onic acid (HA), poly(L-aspa ic acid), poly(L-glu amic acid,)
and poly(sialic acid). Thei esul s e ealed ha liposome-based LbL
nanopa icles showed he highes o simila anspo in T answell®
assay and he highes up ake in b ain mic o ascula endo helial cell line
(hCMEC/D3) monolaye associa ion (Fig. 9c) compa ed o he nano-
pa icles wi h s i e co e. I was also e ealed ha he su ace chemis y
o he LbL nanopa icles de e mines he mechanism by which nano-
pa icles a e anspo ed in acellula ly. A e e alua ing he anspo
in he BBB o mice, liposomal nanopa icles exhibi ed he highes
pe meabili y compa ed o o he LbL nanopa icles wi h he same ou e
laye (Fig. 9d). Finally, liposome-based nanopa icles wi h he las laye
o HA showed he highes pe meabili y in mice BBB compa ed o o he
su ace modi ica ions (Fig. 9e) [243]. Al hough his wo k p o ides
insigh ul esea ch on he e ec o co e s i ness and su ace chemis y
on he capaci y o LbL nanopa icles o c oss he BBB, i is no exac ly
clea why HA unc ionaliza ion imp o ed pe meabili y in i o.
Despi e p e ious a emp s, he e a e ew esea ch wo ks on sel -
assembled nanopa icles ocusing on ca ying biomac omolecules and
c ossing he BBB. The e o e, many mo e s udies a e needed o in es i-
ga e di e en p ospec i e o mula ions using a ious empla es and
su ace chemis ies, de e mine hei e ec i eness, and unco e he eal
po en ial o sel -assembled polyme ic nanoca ie s. Co e emo al a e
laye deposi ion could esul in nanopla o ms wi h mo e elas ic and
luid memb ane ha can pene a e h ough he ba ie [244]. All he
men ioned examples show he e sa ili y and po en ial o sel -assembled
nanoca ie s, including polyme ic micelles, polyme somes, and LbL
nanopa icles/nanocapsules, o combine a ious unc ionali ies in one
sys em o e ec i e deli e y o he apeu ic molecules ac oss he bio-
logical ba ie s, such as he BBB.
3.5. O he polyme ic ca ie s
Nanopa icles based on na u al polyme s like polysaccha ides o
p o eins ha e been explo ed o hei po en ial use in a ge ing BBB and
deli e he apeu ic biomac omolecules [95,245–247]. The p esence o
la ge su ace a eas con aining unc ional g oups (e.g., hyd oxyl,
ca boxyl, amino) allows ailo ing he physicochemical p ope ies o
polyme ic nanoca ie s o enhancing biomolecule conjuga ion and
a ge ing ecep o s o c ossing he BBB. Along wi h his, he size, aspec
a io (shape), su ace cha ge and ligands o he pa icles can also be
modula ed, which also ha e an impo an ole in BBB pene a ion
[248–250]. In his sec ion, we discuss examples o some o he nano-
ca ie s de i ed om na u al polyme s o a ge ed deli e y o d ugs and
s a egies o imp o e hei abili y o c oss he BBB.
Chi osan: Chi osan (CS) is a na u al linea ca ionic copolyme de i ed
om chi in and is a widely used ma e ial o nanoca ie ab ica ion
ha ing p o ound applica ion in many CNS diso de s [251,252]. CS
consis s o β-(1,4)-linked d-glucosamine and N-ace yl-d-glucosamine
g oups. Owing o i s good biocompa ibili y, i is classi ied as ‘gene ally
ecognized as sa e’ (GRAS) by he FDA. CS nanopa icles can be ab i-
ca ed by a ious me hods including ionic gela ion, emulsi ica ion, and
chemical c osslinking [253]. The ionic gela ion me hod was ollowed o
encapsula e me ho exa e, dopamine, and si aglip in d ug o he
ea men o GBM, PD, and AD, espec i ely [251,254,255]. Recen ly,
p oline-loaded CS nanopa icles, syn hesized by ion c osslinking
me hod, ha e been used o deli e p oline, esul ing in neu op o ec ion
a e ischemic inju y [256]. Addi ionally, due o poo pene a ion o
mos o he CNS associa ed d ugs, CS was used o deco a e PLGA and
PCL nanopa icles o a ge ing he d ugs ac oss BBB [251]. The posi i e
su ace-cha ge o he nanopa icles shows high a ini y owa ds he
endo helial cells o enhanced b ain deli e y and cellula adso p ion, ia
AMT. Fo his, CS is modi ied wi h me hyl iodide and glycidyl e he s o
gene a e N- ime hyl CS (TMC) and alkylglyce yl-modi ied CS, espec-
i ely [249]. TMC imp o es mucoadhesion, solubili y (in a
pH-independen manne ), enhances d ug loading and abso p ion e i-
ciency wi h espec o na i e CS. Fo example, nanopa icles o mula ed
wi h TMC loaded wi h an an i-neu oexci a ion pep ide displayed
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Ac a Bioma e ialia 196 (2025) 17–49
35
e ec i e BBB pene a ion, and ha e been used o epilepsy ea men
[251,257]. In case o alkylglyce yl CS, ini ially he p ima y hyd oxyl
unc ionali ies o he low MW CS we e modi ied h ough selec i e
g a ing wi h alkylglyce yl g oups [249,257]. Following his, he
nanopa icles we e syn hesized using ionic gela ion me hod and he
esul ing nanopa icles displayed enhanced pe meabili y o he apeu ics
ac oss BBB [257]. Fu he mo e, he su ace modi ica ion o CS nano-
pa icles wi h PEG has also eme ged as a p omising s a egy o enhance
he b ain a ge ing e iciency o he he apeu ics [257]. To u he
op imize his app oach, he PEG-modi ied nanopa icles we e unc-
ionalized wi h a ge ing an ibodies like OX26 mAb o an i-T R [257].
This a ge ed deli e y s a egy has been used o deli e Z-DEVD-FMK
pep ide and an isense oligonucleo ides, showing imp o ed he apeu ic
e icacy ia RMT [252]. Fo a a ie y o he apeu ic applica ions, CS
nanopa icles ha e also shown p omise o ca y biomac omolecules
ac oss BBB. As an illus a ion, dual an ibody a ge ing siRNA-loaded CS
nanopa icles we e enginee ed o block HIV eplica ion in he CNS [95].
The wo an ibodies T and b adykinin B2 speci ically bind wi h he T R
and b adykinin B2 ecep o , espec i ely, acili a ing siRNA deli e y
in o as ocy e a ge cells. This esul ed in inhibi ion o exp ession o
p o eins such as SART3 and hCycT1 ha a e associa ed wi h HIV
eplica ion [258]. In a simila wo k, CS nanopa icles we e used o in
i o ans ec ion o GFP- agged plasmids on HEK293 (human emb y-
onic kidney cells) and MG-U87 (b ain cance ) cells on mu ine models
[67]. The wo k highligh s he e ec i e BBB pene a ion o CS
nanopa icles.
Algina e: Algina e is a linea unb anched anionic and hyd ophilic
na u al polysaccha ide ob ained om b own seaweed. S uc u ally, i is
composed o a copolyme o
α
-1-gulu onic acid and β-D-mannu onic
acid linked by 1,4-glycosidic moie ies. FDA classi ied algina e as GRAS
due o i s e y good biocompa ibili y and hus, i has widesp ead ap-
plica ions in he ield o d ug and gene deli e y, wound healing, and
issue enginee ing [249]. Repo s ha e shown ha pH- esponsi e algi-
na e nanopa icle o ma ion in ol es me hods like ionic gela ion,
emulsi ica ion-sol en e apo a ion, emulsi ica ion-gela ion, wa e /oil
emulsion me hod, in e -chain c osslinking, o by mixing wi h o he
polyme s [259]. Fo example, algina e nanopa icles ha e been ecen ly
p epa ed along wi h CS o deli e small pep ide SpBMP-9 de i ed om
neu al g ow h ac o BMP-9. This p omo es he di e en ia ion o
choline gic neu ons and inac i a e GSK3be a which a e p omising ou -
comes in he ea men o b ain degene a i e diso de s, such as AD
[260]. The widely used ionic gela ion me hod has been applied o p e-
pa e enla axine-loaded algina e nanopa icles, which ha e been u i-
lized as an i-dep essan s [261]. Following his app oach, an in anasal
ca ie sys em was de eloped, exploi ing elec os a ic in e ac ion o
algina e and doxo ubicin o gi e algina e-doxo ubicin nanocomplex,
which was inco po a ed in o CS nanopa icles. The wo k highligh s he
e icien deli e y o doxo ubicin o b ain issue wi h a a ge ing e i-
ciency o 480%, signi ying a p omising s a egy o in anasal a ge ed
deli e y o he b ain [262]. In ano he example, sodium algina e along
wi h doxo ubicin and hodamine we e emulsi ied in o dioc yl sodium
sul osuccina e [Ae osol OT (AOT)]–algina e nanopa icles and we e
able o o e come P-gp media ed d ug esis ance in umou cells [263].
In ecen p og essions wi hin egene a i e medicine, he ea men o
PD encompasses he deli e y o he apeu ic cells and neu o ophic ac-
o s capable o eleasing dopamine o he b ain. The app oach o
deli e ing cells aims o eplace los neu ons and acili a e unc ional
einne a ion by eleasing dopamine ha sec e es neu o ophic ac o s.
Howe e , clinical ials e ealed high a es o cell dea h pos implan-
a ion. To o e come his, algina e has been used o make dual laye
beads along wi h HA o slow and sus ained elease o he apeu ic cells
SH-SY5Y (neu oblas oma cell line) and immunosupp essan FK506
compound showing p olonged cell su i al and unc ionali y o PD
ea men [264].
Hyalu onic Acid: HA is a wa e soluble, biocompa ible linea poly-
saccha ide composed o D-glucu onic acid and N-ace yl-D-glucosamine
uni s ound in he ex acellula ma ix o a ious issues. The p esence o
hyd oxyl g oups makes i hyd ophilic, whe eas ca boxyl, hyd oxyl, and
ace amido g oups in i s s uc u e can be exploi ed o chemical modi-
ica ion [265]. HA has been ex ensi ely u ilized in d ug deli e y sys ems
due o i s a ini y owa ds CD44 ( ans-memb ane glycop o ein) e-
cep o s ha a e o e exp essed in b eas , lung and me as a ic b ain
cance [266,267]. The syn hesis o nanopa icles in ol es elec os a ic
in e ac ions be ween anionic HA and ca ionic CS, which we e used o
deli e cu cumin and neu oglobin in he b ain o GBM and s oke
ea men [68,268]. Va ious HA-based modi ied nanopla o ms, like
PEGyla ed HA, HA wi h lipoic acid- lysine, HA wi h i amin E succina e
copolyme s, HA wi h glycy he inic acid, doxo ubicin, and sodium i-
polyphospha e nanopa icles ha e been used o doxo ubicin deli e y
o an icance he apy and o e coming chemo esis ance [269]. Fo
enhanced a ge ed he apy o GBM, a hyb id HA nanoca ie sys em
was unc ionalized wi h pep ide HRK-19, con aining RGD and NGR o
bind
α
β3 and aminopep idase-N (CD13) ecep o s o e exp essed in
glioma cells and/o angiogenic essels. Wi h limi ed in es iga ion on he
po en ial use o algina e nanoca ie s, he e is plen y o oom o imp o e
hese nanoca ie s o biomac omolecule deli e y ac oss BBB. Bo h
algina e and HA nanopa icles, being easily designable, and wi h long
ci cula ion ime in he sys emic bloods eam, can be easily modula ed o
achie e enhanced BBB pe mea ion [249–270].
Besides, na u al p o eins a e in ended o se e as ca ie s o a ge ing
moie ies o enhance he anspo o d ugs and he apeu ic agen s o he
CNS [271,272]. P o eins ha ing high s abili y and ac i i y wi h low
enzyma ic deg ada ion, immunogenici y, phagocy osis, enal clea ance,
leading o inc ease in hal -li e o he d ug, has shown p omising ou -
comes [271].
Gela in: Among all na u al polyme s, gela in has been ex ensi ely
used o he deli e y o biomac omolecules o he b ain. The syn hesis o
gela in nanopa icles in ol es emulsi ica ion sol en e apo a ion, des-
ol a ion, nanop ecipi a ion, and mic o luidic de ices me hods [245].
Ideally, gela in needs c osslinking agen s o o e come i s limi a ions o
low mechanical in eg i y and apid decomposi ion. Fo CNS diso de s,
s a egies like ca ionic cell pene a ion based on he pep ide-media ed
endocy osis a e conduc ed o ans e se he BBB. Fo example, a
b ain-pene a ing pep ide conjuga ed wi h PEG and TAT pep ide has
been used o modi ica ion o gela in–siloxane nanopa icles o
enhancing hei e iciency in c ossing BBB [245–252]. Fu he , gela in
nanopa icles ha e demons a ed hei e ec i eness as a eliable ca ie
o RNA deli e y in he b ain en i onmen , along wi h anspo o
g ow h ac o s, mic oRNAs, and siRNA o di e en ia e s em cells and
silence genes [245]. The in anasal deli e y o inducible ni ic oxide
syn hase siRNA and os eopon in pep ide inc eased i s e icacy o he
ea men o ischemic s oke by inducing s ong neu op o ec i e e ec
[245–252]. Recen ly, gela in nanopa icles loaded wi h neu opep ide
Subs ance P deli e ed in CNS enhanced he dopamine gic neu on e-
co e y in hemipa kinsonian a s and can be an e ec i e he apy o PD
[273].
Human Se um Albumin: Human se um albumin (HSA) is a globula
p o ein commonly used o imp o e he solubili y and anspo o hy-
d ophobic d ugs ac oss he BBB. D ug-albumin complexes can inc ease
d ug s abili y and p olong ci cula ion ime, enhancing hei po en ial o
each he CNS. The syn hesis in ol es chemical (emulsion and complex
coace a ion), physical (elec osp ay and nano sp ay), and sel -assembly
(desol a ion) me hods. HSA has eac i e amino, hiol and ca boxylic
g oups on i s su ace, which a ou co alen ligand and su ace modi-
ica ions whe eas hey also a ou non-co alen in e ac ions o a ious
d ugs and pep ides. Albumin nanopa icles unc ionalised wi h he
p o ein ApoE could a ge endo helial cells by ecep o media ed
endocy osis, whe eas nanopa icles wi hou ApoE we e incapable o
eaching b ain issues. Fu he , albumin pa icles can be modi ied wi h
cell pene a ing pep ides like low MW p o amine (LMWP) and b ain
pene a ion enhance s based on adi ional Chinese medicines like
bo neol, muscone o men hol o imp o e BBB pene a ion [274,275]. As
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
36
an illus a ion, BSA nanopa icles and LMWP-modi ied BSA nano-
pa icles we e ab ica ed based on sel -assembly o LMWP and BSA wi h
hyd ophobic d ugs pacli axel and en e inide (Fig. 10a). Bo h ypes o
nanopa icles esul ed in a es ing umou g ow h in bo h subcu aneous
and o ho opic glioma models. In he o ho opic glioma model, he
whole-body imaging da a e ealed up ake o bo h ypes o nanopa icles
(Fig. 10b). No ably, LMWP-modi ied BSA nanopa icles demons a ed
apid and subs an ial accumula ion in b ain wi h highe luo escence
signals (Fig. 10c). In compa ison, he up ake o BSA nanopa icles was
no ably lowe han ha o he LMWP (Figs. 10c and e). The esul s a e
u he co obo a ed wi h ex i o imaging o he dissec ed o gans om
mice (Fig. 10d). A majo disad an age o his model is he lack o BBB.
Cu en ly, o GBM, clinical ials a e going on wi h FDA app o ed
Ab axane (albumin bound pacli axel) along wi h ca bopla in and
implan ed ul asound emi e s de ice [246]. Fu he , albumin is used o
modi y he su ace o polyme ic nanopa icles o enhancing BBB
ansloca ion [246].
Fu he , modi ica ions o nanopa icles wi h na u al ligands/
Fig. 10. Blood-b ain ba ie (BBB) pene a ing low molecula weigh p o amine (LMWP) bo ine se um albumin (BSA) nanopa icles (L-BSA-NPs) and BSA-NPs
de eloped wi h sel -assembly o LMWP and BSA along wi h hyd ophobic d ugs pacli axel (PTX) and en e inide(4-HPR). Cha ac e iza ion o he syn hesized BSA-
NPs and L-BSA-NPs. (A) T ansmission elec on mic og aphy and he pa icle size dis ibu ion o he BSA-NPs and L-BSA-NPs. (B) In i o imaging o mice bea ing
U87 xenog a umou s showing in e umo al pene a ion abili y o BSA-NPs and L-BSA-NPs. Full body imaging showing biodis ibu ion o BSA-NPs and L-BSA-NPs,
wi h p og essi e ise in luo escen in ensi y om 2 o 8 h, wi h L-BSA-NPs displaying enhanced umo accumula ion compa ed o BSA-NPs. (C) Quan i ica ion o he
a e age luo escence e iciency in i o a he umo si e. (D) Ex i o imaging o he majo dissec ed o gans, whe e umo shows highe luo escence in ensi y. (E)
Quan i ica ion o luo escence in ensi y o only umou s om D. Adap ed wi h pe mission om [274]. Copy igh © 2016 Ame ican Chemical Socie y.
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
37

p o eins like T , lac o e in, apolipop o ein, and melanoT ha e been
success ully used o a ge he exp essed ecep o s on endo helial cells
and imp o e BBB anscy osis [249,252]. T is a glycop o ein ha in-
e ac s wi h T R o e exp essed on he su ace o BBB h ough
ligand- ecep o ecogni ion. Addi ionally, nanoca ie made om na -
u al i on s o age p o ein, e i in, exhibi s BBB- a e sing and he
glioma- a ge ing p ope ies. Fe i in nanoca ie s along wi h hei
modi ica ion wi h in eg in
α
2β1 a ge ing ligand (DGEAGGDGEA) ha e
been used o deli e doxo ubicin o enhanced o ho opic glioma he -
apy [276].
Ad ances in ma e ial chemis y ha e sugges i ely augmen ed he
polyme ic nanoca ie s o mula ions and i s usage in CNS deli e y. The
na u ally occu ing polyme s owing o i s less oxici y, biocompa ibili y,
a ge ed d ug deli e y, e sa ili y, biodeg adabili y, a ailabili y, and
low cos o e g ea p omise o imp o ing d ug deli e y ac oss he BBB.
Howe e , due o hei low mechanical s eng h, polyme ic nanoca ie s
ha e poo s abili y and s uc u al in eg i y du ing ci cula ion and d ug
leakage compa ed o syn he ic polyme s. Fu he , challenges like apid
clea ance, ba ch o ba ch a iabili y, lowe d ug encapsula ion and
po en ial immunogenici y should be ca e ully conside ed in he a ional
designed o s a egies o acili a e d ug anspo a ion ac oss he BBB o
po en ial long- e m and clinical applica ion.
4. Clinical ansla ion
Basic and applied neu oscience has b ough o ligh new echnolo-
gies and he disco e y o new he apeu ic in e en ions wi h po en ial o
o e come some o he majo CNS diso de s. Fu he mo e, an inc easing
in-dep h unde s anding and desc ip ion o new molecula a ge s o CNS
diso de s is also enhancing he oolbox o he design o new he apies.
Hence, bo h academia and indus y e o s a e ocused on he wo ldwide
bu den o he neu ological diso de s in he las decades, which ep esen
he leading cause o disabili y and he second leading cause o dea h
[277]. Cases o b ain cance as well as he p e alence o CNS diso de s
a e inc easing due o he longe li e-expec ancy acco ding o Wo ld
Heal h O ganiza ion. Howe e , some p ac ical challenges emain in
es ablishing no el d ugs and biologicals when mo ing om he bench o
in i o s udies o in o he clinical use. Eme ging app oaches, such as
in anasal deli e y, a e being implemen ed as a non-in asi e op ion o
he d ug deli e y o he CNS while educing pe iphe al exposu e, mos ly
a a basic esea ch le el. Thus, de eloping new s a egies o each he
CNS, while limi ing sys emic e ec s is s ill one o he main clinical
challenges due o he inhe en high complexi y o he BBB. Decades o
neu oscience esea ch ha e led o he de elopmen o biologic d ugs
ha ha e gi en clinicians and pa ien s enewed hope o imp o ed
ea men op ions o complex diseases like MS, AD, PD, o b ain can-
ce s, among o he s. The de elopmen and use o biomac omolecules a e
blossoming in he las yea s due o hei abili y o a ge speci ic pa h-
ways, which educes undesi ed side e ec s, also allowing o pe sonal-
ized ea men ha add esses he pa ien ’s pa icula condi ion.
Al hough he a ailabili y o biologic ea men s o CNS diso de s is
limi ed, he e is no denying ha he exis ing adi ional d ugs unda-
men ally change symp oms o hese diseases bu do no change he
ch onic onse o he diso de . Mos o he a ailable he apeu ic bio-
mac omolecules in he ma ke a e an ibodies, such as LEMTRADA®
(alem uzumab), TYSABRI® (na alizumab), o OCREVUS® (oc elizu-
mab) o he ea men o MS, Aduhelm® (aducanumab) o AD, and
Be acizumab o Naxi amab-gqgk o b ain cance . Rega dless o he
pa hology, clinical ials ha e ailed o a mul i ude o easons, such as
se e e ad e se e ec s, minimal o no change in disease onse o poo
bioa ailabili y due o he inhe en complexi y o he diso de s and he
BBB c ossing abili y [278]. Howe e , he inc easing numbe o people
a ec ed by CNS diso de s and b ain umo s poin ou he need o new
de elopmen s o ackle his global bu den, especially in low and
mid-income coun ies. Fu he mo e, abou one hi d o he FDA ap-
p o als in 2022 we e biologics, pushing hem ahead o small molecules
o he i s ime, wi h new app oaches such as an ibody–d ug conju-
ga es, bispeci ic p o eins, and cell and gene he apies [279]. This end is
e idenced wi h mo e han 300 en ies o “Alzheime ’s Disease and
enzymes”, 34 en ies o “mul iple scle osis and g ow h ac o s”, 127
en ies o “neu oblas oma and an ibody”, o 63 en ies o “GBM and
an ibodies”, in he websi e clinical ials.go among o he s. When
sea ching o ials in ol ing “nanopa icles”, he numbe s dec ease
d ama ically, being mos ly ocused on he use o me allic nanopa icles
and liposomes (Table 5). The i s liposomal based d ug, Doxil, was
app o ed by he FDA in 1995, while he i s polyme ic nanopa icle,
Ab axane, go he app o al in 2005 bo h using small molecules as hei
ca goes [280]. Two decades la e , he FDA app o ed a nanome ic
ca ie based on Lipid and Nucleic acids, called ONPATTRO®. In addi-
ion, PEGyla ion echnology has been widely applied o e he las 30
yea s o imp o e he pha macokine ics and pha macodynamics o
di e en he apeu ic modali ies such as small molecules, pep ides, o
p o eins, which leads o o e 30 PEGyla ed d ugs cu en ly used in he
clinic [281]. Fu he mo e, some clinical ials a e ocused on he use o
Ab axane o Doxil on d ug epu posing app oaches nowadays (Table 5).
O e all, i is expec ed ha he endency o using biomac omolecules
ollow up o he use o polyme ic nanoca ie s loading hem o o e come
hei inhe en ly poo physicochemical p ope ies in he upcoming yea s.
5. Pi alls and u u e pe spec i es
As explained along his e iew, a ge ed nanopa icles ha e shown
p omise o o e come he BBB. Howe e , hey also accumula e and
elease he ca go in o - a ge body si es, which o en esul s in sys emic
side e ec s. Nasal adminis a ion was ini ially u ilized o local d ug
deli e y in he ea men o alle gic condi ions and sys emic adminis-
a ion in he so-called ansnasal ou e [282]. Fo example, calci onin
salmon nasal sp ay is used o ea pos menopausal os eopo osis. The
ansnasal deli e y o o he biologicals such as he human g ow h ac o
and oxy ocin has been also in es iga ed [283,284]. The ansnasal ou e
bypasses hepa ic i s -pass me abolism and could lead o sys emic
bioa ailabili y compa able o he in a enous and he in amuscula
injec ions. An adminis a ion s a egy ha capi alizes on di ec ans-
po mechanisms be ween he ol ac o y nasal epi helium and he CNS,
namely he in anasal o nose- o-b ain ou e, was in oduced by P o . W.
H. F ey II in he 1990s o he deli e y o pep ides and o he he apeu ic
molecules [285–288]. Majo ad an ages a e he quick onse o ac ion, no
hepa ic i s -pass me abolism, and pa ien compliance. Daun less e o s
ha e been de o ed o un a el he molecula and cellula pa hways
in ol ed in he nose- o-b ain anspo , which a e s ill unde scien i ic
deba e [289]. The anspo is an in e play among di e en in acellula
and ex acellula mechanisms wi h a le el o con ibu ion ha depends
on he p ope ies o he d ug (in solu ion o as a nanopa icle) and he
o mula ion. O e all, he e is b oad ag eemen ha he ol ac o y egion
in gene al and he ol ac o y neu ons in pa icula play a key ole [290,
291]. Also b anches o he igeminal ne e a e ele an playe s as
neu ons om hese b anches connec he nasal mucosa wi h he ol ac-
o y bulb. In addi ion, he apeu ic compound can access he b ain ia
he blood ascula u e and he lympha ic sys em. The possible ole o
mic oglia in he nose- o-b ain anspo o di e en ypes o nano-
pa icles has been ecen ly epo ed [292,293]. I is wo h s essing ha
he egion o he CNS in which he nanopa icles accumula e depends on
ea u es such as size and su ace chemis y [197]. Thus, a mo e
comp ehensi e in es iga ion o his pa hway has o be ca ied ou o
which he de elopmen o clinically ele an in i o and ex i o models
ha will enable he sc eening o he mos p omising p o o ypes is a
c ucial s age [197–294].
The de elopmen o in i o models ha ai h ully ecapi ula e he
complexi y o he BBB and allow a apid sc eening o he apeu ics has
been also placed in he spo ligh o many in es iga ions. These models
a e belie ed o ci cum en , o a leas minimize, he need o in i o
models in he nea u u e, being in line wi h he 3R p inciples ( eplace,
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
38
Table 5
Ongoing clinical ials using nanopa icles o ea CNS diso de s o b ain cance .
S udy Ti le Phase Sys em Disease G oups Pa icipan s P ima y Ou come S a us Iden i ie
High-Field MRI I on-
Based Con as -
Enhanced
Cha ac e iza ion o
Mul iple Scle osis and
Demyelina ing
Diseases
NA Fe aheme
( e umoxy ol)
RRMS In e en ions: D ug:
Fe aheme
D ug: Gadolinium-based
con as
NA Numbe and loca ion o
enhancing b ain lesions
seen on 7 esla MRI
ollowing Fe aheme
adminis a ion.
Wi hd awn NCT01973517
In Vi o Cha ac e iza ion
o In lamma ion Wi h
Fe umoxy ol, an
Ul asmall
Supe pa amagne ic
I on Oxide
Nanopa icle, on 7
Tesla Magne ic
Resonance Imaging
1 Fe umoxy ol, an
Ul asmall
Supe pa amagne ic
I on Oxide
Nanopa icle
MS Expe imen al:
Fe umoxy ol
A 510 mg dose (17 mL) o
e umoxy ol dilu ed in
50 mL o 0.9% no mal
saline will be
in a enous
14 To de e mine he
change in g adien -echo
T2*-weigh ed signal in
an i on- ich b ain
s uc u e, he globus
pallidus [Time F ame: 6
mon hs ollowing
e umoxy ol
adminis a ion]
de e mine i
e umoxy ol induces
long-las ing b ain signal
in ensi y changes in HV
and MS
Comple ed NCT02511028
No el Imaging Ma ke s
in SPMS
1 Fe umoxy ol SPMS D ug: Fe umoxy ol
in usion
D ug: Gado e idol
Diagnos ic Tes : MRI
B ain and Ce ical Spine
10 To de e mine a signal
change on T1-weigh ed
and 3D UTE MRI b ain
(and uppe ce ical
co d) be o e and 96
hou s (±24 hou s) a e
e umoxy ol
adminis a ion [Time
F ame: 96 hou s ±24
hou s]
Rec ui ing NCT05357833
31P-MRS Imaging o
Assess he E ec s o
CNM-Au8 on
Impai ed Neu onal
Redox S a e in
Mul iple Scle osis.
(REPAIR-MS)
2 CNM-Au8 (Gold
Nanoc ys als)
MS
PD
In e en ions: D ug: gold
nanoc ys als
Expe imen al: 60mg
CNM-Au8
60mg suspension o
clean-su aced, ace ed,
gold nanoc ys als in
120ml o sodium
bica bona e bu e ed
wa e
In e en ions: D ug: gold
nanoc ys als
NA The change om
baseline o week 12 in
CNS me abolic changes,
based on 31P-MRS
Redox Ra io. [Time
F ame: A 12 Weeks]
Rec ui ing
Comple ed
NCT03993171
NCT03815916
The apeu ic
Nanoca alysis o Slow
Disease P og ession o
Amyo ophic La e al
Scle osis (ALS)
(RESCUE-ALS)
2 CNM-Au8 ALS D ug: CNM-Au8
D ug: Placebo
45 Elec omyog aphy
measu es o disease
p og ession. [Time
F ame: 36 weeks]
Comple ed NCT04098406
S udy o APH-1105 in
Pa ien s Wi h Mild o
Mode a e Alzheime ’s
Disease
2 APH-1105 (Alpha
Sec e ase Modula o )
AD D ug: APH-1105
O he : Placebo
NA Sa e y: Incidence o
T ea men -eme gen
Ad e se E en s [Time
F ame: Baseline
h ough 30 days pos
inal ea men dose up
o day 60]
E icacy: Cogni ion
Change [Time F ame:
Baseline - day 60]
Change in Alzheime ’s
Disease Assessmen
Scale-Cog (ADAS-COG)
o al sco e om
baseline o pos inal
ea men dose.
No ye
ec ui ing
NCT03806478
Radiosensi iza ion o
Mul iple B ain
Me as ases Using
AGuIX Gadolinium
Based Nanopa icles
(NANO-RAD)
1 AGuIX®
Gadolinium chela ed
polysiloxane based
nanopa icles wi h
Magne ic Resonance
B ain
Cance
In e en ions: D ug:
AGuIX
Radia ion: whole b ain
adia ion he apy
15 Maximum- ole a ed
dose (MTD) o
polysiloxane
gadolinium-chela es
based nanopa icles
(AGuIX) gi en
concu en ly o he
whole b ain adia ion
he apy o he
Comple ed NCT02820454
(con inued on nex page)
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
39
Table 5 (con inued)
S udy Ti le Phase Sys em Disease G oups Pa icipan s P ima y Ou come S a us Iden i ie
ea men o mul iple
b ain me as ases [Time
F ame: 18 mon hs]
E alua ing AGuIX®
Nanopa icles in
Combina ion Wi h
S e eo ac ic Radia ion
o B ain Me as ases
(NANOSTEREO)
2 AGuIX®B ain
Cance
D ug: AGuIX
2 IV injec ions (100 mg/
Kg/injec ion) a day 4
and day 8 +S e eo ac ic
Radia ion om day 8 o
day 15 as pe s anda d
p ac ice.
1 Ra e o local con ol
[Time F ame: 1 yea ]
The p ima y endpoin is
he a e o local con ol
de ined as he
p opo ion o pa ien s
wi h a comple e
esponse, a pa ial
esponse o a s able
disease.
Te mina ed NCT04094077
S e eo ac ic B ain-
di ec ed Radia ion
Wi h o Wi hou
Aguix Gadolinium-
Based Nanopa icles
in B ain Me as ases
2 AGuIX®B ain
Cance
Radia ion: S e eo ac ic
Radia ion
D ug: AGuIX
gadolinium-based
nanopa icles
Radia ion: S e eo ac ic
Radia ion
O he : Placebo
134 Local Recu ence [Time
F ame: F om
en ollmen o 6 mon hs]
Assessed wi h Response
Assessmen in Neu o-
Oncology (RANO) -
B ain Me as asis
Guidelines Time o local
ailu e on a pe
me as asis basis will be
pe o med using he
log- ank es .
Rec ui ing NCT04899908
Radio he apy o
Mul iple B ain
Me as ases Using
AGuIX®
(NANORAD2)
2 AGuIX®B ain
Cance
In e en ions: D ug:
AGuIX®
Radia ion: Whole B ain
Radia ion The apy
In e en ions: Radia ion:
Whole B ain Radia ion
The apy
NA E alua ion o b ain
me as ases esponse,
acco ding o RECIST
1.1 c i e ia (o
modi ied RECIST) by
MRI, wi h MRI
cen alized eading
Rec ui ing NCT03818386
Pemb o+Chemo in
B ain Me s
2 Nab-Pacli axel B ain
Cance
Pemb olizumab wi h
s anda d o ca e
chemo he apy
ea men : Pa ien s will
ecei e 200mg o 400mg
o Pemb olizumab
(s anda d o ca e dosing
a he disc e ion o
ea ing physician) e e y
h ee o six weeks wi h
s anda d o ca e
chemo he apy ea men
(ca bopla in,
peme exed, pacli axel,
nab-pacli axel).
In e en ions: D ug:
Pemb olizumab
D ug: Nab pacli axel
D ug: Pacli axel
D ug: Peme exed
D ug: Ca bopla in
NA Disease con ol a e
[Time F ame: 6 mon hs
(baseline o 6 mon hs)]
In ac anial bene i
de ined as s able
disease, pa ial
esponse, and comple e
esponse
Rec ui ing NCT04964960
Lapa inib and Pacli axel
in T ea ing Pa ien s
Wi h Ad anced Solid
Tumo s
1 Ab axane B ain
Cance
D ug: lapa inib
D ug: pacli axel
albumin-s abilized
nanopa icle o mula ion
Ab axane
28 Maximum ole a ed
dose (MTD) o lapa inib
in cou se 1 [Time
F ame: es ima ed o be
12 weeks]
Comple ed NCT00313599
MTX110 by Con ec ion-
Enhanced Deli e y in
T ea ing Pa icipan s
Wi h Newly-
Diagnosed Di use
In insic Pon ine
Glioma (PNOC015)
1 and
2
MTX110 (panobinos a
nanopa icle
o mula ion)
B ain
Cance
In e en ions: D ug:
Panobinos a
Nanopa icle
Fo mula ion MTX110
D ug: Con ec ion-
Enhanced Deli e y
(CED)
7 Ad e se e en s and
clinically signi ican
labo a o y
abno mali ies which
mee G ade 3, 4, o 5
c i e ia acco ding o
Common Te minology
C i e ia o Ad e se
E en s (CTCAE)
Comple ed NCT03566199
CED o MTX110 Newly
Diagnosed Di use
Midline Gliomas
1 MTX110 B ain
Cance
In e en ions: D ug:
In usa e wi h MTX110
and gadolinium
De ice: Con ec ion-
Enhanced Deli e y
(CED)
NA Sa e y o epea ed
con ec ion-enhanced
deli e y (CED) o
MTX110 will be
epo ed by
summa izing he
incidence a e o
ad e se e en s obse ed
o epo ed.
Rec ui ing NCT04264143
(con inued on nex page)
E. Rome o-Ben e al.
Ac a Bioma e ialia 196 (2025) 17–49
40
educe, e ine) and acili a ing he p e-clinical selec ion o BBB-
pe meable he apeu ics [295]. As explained along his e iew, he BBB
is a he e ocellula ba ie , in which he c oss alk be ween he di e en
cell ypes and he cha ac e is ics o he ex acellula ma ix play an
impo an ole. Thus, esembling his complex scena io in i o is
challenging. Mos o he s udies epo ed in li e a u e ely on he use o
wo-dimensional models. The complexi y o hese wo-dimensional
models can be u he expanded by including a ious cell ypes (e.g.,
pe icy es, as ocy es, neu ons) ei he p ima y, es ablished cell lines o
de i ed om induced plu ipo en s em cells (iPSCs) [296,297]. These
models ha e gained popula i y hanks o hei simplici y and possibili y
o ob ain p elimina y esul s in a ela i ely sho pe iod o ime. How-
e e , hey poo ly ep esen he mo phological ea u es o b ain capil-
la ies in e ms o geome y and s uc u al o ganiza ion. Besides, he
semipo ous memb ane is made ou o igid polyme s (e.g., poly-
ca bona e o polye hylene e eph hala e) wi h mechanical s i ness a
abo e he ones obse ed in he ex acellula ma ix. The e o e, e-
sea che s a e ying o combine he simplici y o hese wo-dimensional
models wi h mo e biomime ic memb anes o achie e pe meabili y
alues close o he in i o scena io [298]. The use o mic o luidics has
eme ged as a po en ool o de elop mo e clinically ele an BBB models.
Mic o luidic de ices usually con ain in e connec ed compa men s ha
allow he cocul u e o di e en cell ypes in indi idual chambe s.
Mo eo e , hese compa men s can be illed wi h cell-laden gels, hus
c ea ing a 3-dimensonal en i onmen ha be e ep esen he physio-
logical cell o ganiza ion [299,300]. The use o mic o luidic de ices,
oge he wi h he es ablishmen o imp o ed in i o cul u e p o ocols,
he use o human iPSCs and he possibili y o mimic physiological
condi ions (e.g., luid shea s ess, blood-like iscosi y) a e allowing he
de elopmen o obus in i o pla o ms ha ep esen a eal al e na i e
o in i o models. As an illus a ion, Pa k e al. epo ed a mic o luidic
chip ha main ained human BBB unc ion (i.e., low ba ie pe me-
abili y, exp ession o e lux pumps, high le els o TJs) o up o one week
in i o, and showed in i o-like selec i e anscy osis o pep ides and
an ibodies [301]. Al e na i e models exploi he capaci y o cells o
sel -assemble in o h ee-dimensional essel a chi ec u es. Fo example,
he cocul u e o human endo helial cells, as ocy es and pe icy es wi hin
ib in gels esul ed in he o ma ion o a mic o ascula ne wo k ha
shows gene exp ession p o iles and pe meabili y alues simila o hose
obse ed in i o [302,303].
As explained be o e, his e iew examines a ious polyme ca ie s
sui able o deli e ing biomac omolecules o he b ain. These ca ie s
ha e been de eloped using a ial-and-e o -based app oach, which is
cu en ly a signi ican bo leneck in he de elopmen o polyme ic
Table 5 (con inued)
S udy Ti le Phase Sys em Disease G oups Pa icipan s P ima y Ou come S a us Iden i ie
Maximum Tole a ed
Dose (MTD) o MTX110
[Time F ame: 14 days]
A S udy o E alua e he
Sa e y, Tole abili y
and Immunogenici y
o EGFR(V)-EDV-Dox
in Subjec s Wi h
Recu en GBM
(Ce eb alEDV)
1 EGFR(V)-EDV-Dox
((V)EDVDox con ains
doxo ubicin (Dox)
wi hin he minicells
and a ge s EGFR
h ough Vec ibix)
B ain
Cance
GBM
In e en ions: D ug:
EGFR(V)-EDV-Dox
NA Sa e y measu es will be
conduc ed om S udy
Day 1 as pe s udy
schedule o sa e y
ollow-up isi 30 (+5
days) pos las dose.
Unknown NCT02766699
AGuIX Nanopa icles
Wi h Radio he apy
Plus Concomi an
Temozolomide in he
T ea men o Newly
Diagnosed GBM
(NANO-GBM)
1 and
2
AGuIX®GBM Expe imen al: AGuIX +
chemo adio he apy
( adio he apy +
emozolomide)
Sham Compa a o :
chemo adio he apy
( adio he apy +
emozolomide)
NA The ecommended dose
(phase I) o AGuIX in
combina ion wi h TMZ
and and adio he apy
du ing he adio-
chemo he apy pe iod
[Time F ame: du ing 6
weeks a e he i s
injec ion o AGuIX]
6-mon h P og ession
F ee Su i al (PFS) a e
(phase II) [Time F ame:
6 mon hs om he s a
o ea men ]
Rec ui ing NCT04881032
Phase II S udy o
Combined
Temozolomide and
SGT-53 o T ea men
o Recu en GBM
2 SGT-53 (a complex o
ca ionic liposome
encapsula ing a no mal
human wild ype p53
DNA sequence in a
plasmid backbone)
GBM In e en ions: Gene ic:
SGT-53
D ug: Temozolomide
1 Tumo Response [Time
F ame: 6 mon hs]
The 6-mon h
p og ession- ee
su i al (PFS) was
e alua ed using RANO
Response C i e ia.
Te mina ed NCT02340156
NU-0129 in T ea ing
Pa ien s Wi h
Recu en GBM o
Gliosa coma
Unde going Su ge y
1 NU-0129 (gold base
sphe ical nucleic acid
(SNA) nanoconjuga e
a ge ing BCL2L12)
GBM Expe imen al: T ea men
(NU-0129)
8 To e alua e he sa e y o
in a enous NU-0129 in
pa ien s wi h ecu en
GBM o GS.
Comple ed NCT03020017
A Phase I T ial o
Nanoliposomal CPT-
11 (NL CPT-11) in
Pa ien s Wi h
Recu en High-G ade
Gliomas
1 NL CPT-11 GBM In e en ions: D ug:
Nanoliposomal CPT-11
34 To assess he sa e y and
pha macokine ics o NL
CPT-11 in pa ien s wi h
ecu en malignan
glioma s a i ied based
on UGT1A1 geno yping.
[Time F ame: 1–2
yea s]
Comple ed NCT00734682
(Da a om: h ps://clinical ials.go ). T ials wi h jus expec ed numbe o pa icipan s we e conside ed as no applicable (NA). Abb e ia ions: MS, Mul iple Scle osis;
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