TABLE 1.

Summary of functionalized polymeric NPs and their potential advantages.

Functionalization	Polymer	Reaction	Advantages	References
Abs anti Tfr-1	Chitosan	Electrostatic interaction	To mediate transcytosis and deliver neuroprotective peptides into the brain of injured mouse models	Yemisci et al., 2015
Abs anti-Aβ1–42	PACA	CuAAC	To enable specific targeting to Aβ1–42 peptides for inhibiting their aggregation and for rescuing their toxicity effect	Le Droumaguet et al., 2012
Amino groups	PS	Free-radical polymerization in emulsion	To modulate mTOR signaling	Loos et al., 2014a
Azide and alkyne units	PGA	CuAAC	To increase drug transport across the BBB showing neuroprotective effects similar to those of neuroprotective drugs	Duro-Castano et al., 2021
B6 peptide	PEG-PLA	Thiol- maleimide	To increase BBB permeability via lipid raft-mediated and clathrin-mediated endocytosis To inhibit Aβ aggregation and disaggregate preformed Aβ fibrils	Liu et al., 2013a; Yin et al., 2015
Boronate	Polyphenols	Catechol-boronate complexation	To improve the bioactivity of delivered proteins after their intracellular release	Wang et al., 2020
BSA and cationized BSA	PEG-PLA	EDC	To increase their internalization by the brain endothelial cells. cBSA accumulation is much higher than BSA-NPs	Parikh et al., 2010
Carboxyl groups	PS	Free-radical polymerization in emulsion	To increase internalization time in macrophages	Loos et al., 2014b
Chitosan	PLGA PCL- triblock surfactant poloxamer (PEO–PPO–PEO)	Electrostatic interaction Physical interactions	To increase plasma stability, drug efficacy and safety To increase plasma stability, drug efficacy and safety	Guo and Gemeinhart, 2008; Mazzarino et al., 2012; Qian et al., 2013
Curcumin–phospholipid conjugate	DPPC/Cholesterol + DPS-curcumin	Michael addition using DPSH and DIPEA	To specifically label Aβ deposits in vivo both in AD mouse brains and human post-mortem AD brains	Lazar et al., 2013
EGCG (green tea polyphenol epigallocatechin-3-gallate)	Poly succinimide	Schiff’s base	To promote the non-amyloidogenic processing of the APP in AD mice	Rezai-Zadeh et al., 2005; Obregon et al., 2006
Oxidized EGCG	Poly succinimide	Schiff’s base	To increase extracellular and intracellular anti-amyloidogenic effect by 10–100 times	Debnath et al., 2016
Hydroxypropyl β-cyclodextrin	PEG-PLA co-block and PVP (as stabilizer)	Physical interactions	To cryoprotect the drug (curcumin) during the NP freeze drying, preserving the therapeutic activities of the nanoformulates; suitable to reduce Aβ plaque burden in AD mouse brains and to improve cue and working memory	Cheng et al., 2013
Insulin	Poly (N-vinyl pyrrolidone)	EDC	To protect from protease degradation and bind to insulin receptors	Picone et al., 2016
Lactoferrin	PEG-PCL	Thiol-maleimide	To facilitate the nose-to-brain drug delivery of neuroprotective peptides	Liu et al., 2013b
PEG and GSH	PLGA	Thiol-maleimide	To increase the uptake by neuronal cells; the presence of GSH has a better neuroprotective effect; to avoid lysosomal degradation and increase therapeutic fate of delivered drugs	Paka and Ramassamy, 2017
Peptide cRGDfK and nanobody 11A4	PLGA	Thiol-maleimide	To tune cellular internalization by targeting cell surface receptors	Martínez-Jothar et al., 2018
Poly (α, β-aspartic acid) with glucose conjugated	PEG	Self-assembling	To increase and selectively control the transport of bioactive substances into the brain via GLUT1	Anraku et al., 2017
Polysorbate 80	Poly(butyl cyano-acrylate) Chitosan	Physical interaction Physical interaction	To facilitate BBB crossing and increase drug uptake To facilitate BBB crossing and increase drug uptake	Wilson et al., 2008a,Wilson et al., 2010, 2011; Kreuter et al., 2002; Koffie et al., 2011
Proteins	Polyphenols	Schiff’s base	To enhance intracellular protein delivery	Wang et al., 2020
Radioligand (PBR28 derivative)	PCL	CuAAC	High capacity of brain penetration and high selectivity for 18 kDa translocator protein (TSPO) for monitoring microgliosis	Auriemma et al., 2021
SATO	FBEA	Oxime chemistry	Neuroprotection and slow-down of AD progression	Carrazzone et al., 2020
Sialic acid mimetics	PLGA	EDC	To improve binding ability to Siglec-3, counteracting the Aβ protein deposition and plaque formation	Yin et al., 2015; Büll et al., 2016
Simvastatin and citicoline	Chitosan	EDC	To counteract the potential secondary side-effects of simvastatin through the neuroprotective and psychostimulant action of citicoline	Mozafari et al., 2020
Tet-1 peptide	PLGA	EDC	To enhance the uptake by neuronal cells and promote a neuronal- targeted therapeutic approach	Mathew et al., 2012; Bhatt et al., 2017
Trimethylated chitosan (TMC)	PLGA	EDC	To enhance drug delivery and cellular uptake with low toxicity	Wang et al., 2010