Table 1.

Summary of the presented nanosystems for GBM targeting.

NP Type	Targeting Moiety	Target	Key Results	Ref.
Crosslinked peptide	MPC	Acetylcholine transporter	Successful delivery of nimotuzumab in orthotopic glioma xenograft mice	[32]
Liposomes	ApoE derived peptide + chlorotoxin	Lipid transport	Doxorubicin loaded into the liposomes produced reduced viability of GBM U87 cells and did not affect endothelial cells in vitro	[33]
Nano-immune conjugate	Tf Receptor antibody	Tf receptor	PMLA backbone conjugated to Tf Receptor antibody for targeting and CTLA-4 and PD-1 antibodies. The system was able to induce antitumor immune response in GBM mice	[34]
PEGylated liposomes	ITGA2 antibody	ITGA2	Doxorubicin loaded liposomes were able to cross the BBTB but not the healthy BBB. ITGA2 blocked GBM cell migration	[39]
PLGA NPs	M08 antibody	Cell surface vimentin	NPs loaded with paclitaxel showed increased apoptosis in GBM cells compared to healthy astrocytes	[40]
Porous silica NPs	SIWV peptide	Caveolin-mediated transport	Accumulation of NPs in the brain of mice with GBM xenografts, resulting in prolonged survival, with higher GBM selectivity in vitro than in vivo	[42,43]
Lipid-CaP NPs	CTCE9908 peptide	CXCR4	Efficient delivery of siRNA in GBM cultures and GBM mice, resulting in silencing of the PD-1 gene ligand	[45]
PEG–PCL NPs	WGA + FA	Sialic acid + FA receptor	NPs were loaded with different anticancer drugs, and the double-ligand strategy showed improved targeting efficacy compared to the single moieties in vitro	[46]
PEGylated liposomes	VAP + p-HA	GRP78 protein + dopamine receptors	Enhanced BBB crossing and GBM accumulation in spheroids Apoptotic and antiangiogenic effect in orthotopic GBM mice	[47]
PEGylated liposomes	RGD + Lf	Integrin αvβ3 + Lf receptor	Improved BBB crossing and GBM accumulation in spheroids Improved efficacy of docetaxel in vivo compared to nontargeted liposomes	[49]
Polymeric micelles	ST-RAP12 peptide	LRP1 receptor	The peptide improved GBM specificity of paclitaxel-loaded micelles, with increased survival rate and inhibited angiogenesis in vivo	[50]
DSPE–PEG micelles	DATP	Neuropeptide Y receptor Y1	Increased BBB crossing in vitro compared to other known ligands The ATP peptide improved photothermal therapy in vivo	[51]
PEGylated liposomes	RVG15 peptide	Nicotinic acetylcholine receptor	Improved delivery of paclitaxel across the BBB and accumulation in GBM cells in vivo Inhibition of tumor growth and metastases formation	[53]
Liposomes	mnRwr peptide	Integrin αvβ3	Increased penetration in tumor spheroids compared to RGD peptide, and increased accumulation in GBM mice	[54]
PEI-coated silica NPs	T10 peptide	Tf receptor	Induced formation of a Tf corona on the surface of NPs to target the Tf Receptor Efficient BBB crossing and GBM targeting in vivo with prolonged release of doxorubicin	[55]
Albumin NPs	Collagenase	Extracellular matrix	Efficient delivery of gemcitabine in tumor spheroids	[56]
Liposomes	EGF	EGF receptor	Increased delivery of silver NPs loaded into liposomes, specifically to GBM cells in vitro	[57]
Albumin NPs	Scavenger receptor A + SPARC protein	TAMs in TME	Improved ICB therapy with elimination of TAMs from the TME	[58]
Copper–selenium NPs	Biomimetic cell membrane	TME	Shift of TAMs to an M1 phenotype, decreased expression of the PD-1 ligand, and increase in memory T cells	[59]
Albumin NPs	ROS-sensitive linker + PD-1 ligand antibody	ROS in TME	System enclosed in a hydrogel together with iron oxide NPs for combined photodynamic therapy and immunomodulation	[60]
Platinum NPs + dextran NPs	Linkage via pH -sensitive borate ester	Acidic pH in TME	Disassembly of the two NPs improved penetration into GBM and release of loaded sotuletinib to eliminate TAMs	[61]

Abbreviations: BBB—blood-brain barrier; BBTB—blood-brain tumor barrier; CaP—calcium phosphate; EGF—epidermal growth factor; FA—folic acid; GBM—glioblastoma multiforme; ICB—immune checkpoint blockade; Lf—lactoferrin; MPC—2-methacryloyloxyethyl phosphorylcholine; NPs—nanoparticles; PD-1—programmed cell death 1- (ligand, antibody, etc); PEG-PCL—poly(ethylene glycol)–poly(ε-caprolactone); PEI—polyethyleneimine; p-HA—p-hydroxybenzoic acid; PMLA—poly(β-L-malic acid); ROS—reactive oxygen species; TAMs—tumor-associated macrophages; Tf—transferrin; TME—tumor microenvironment; VEGF—vascular endothelial growth factor; WGA—wheat germ agglutinin.