Peptide-Hitchhiking for the Development of Nanosystems in Glioblastoma

Abstract

Glioblastoma (GBM) remains the epitome of aggressiveness and lethality in the spectrum of brain tumors, primarily due to the blood-brain barrier (BBB) that hinders effective treatment delivery, tumor heterogeneity, and the presence of treatment-resistant stem cells that contribute to tumor recurrence. Nanoparticles (NPs) have been used to overcome these obstacles by attaching targeting ligands to enhance therapeutic efficacy. Among these ligands, peptides stand out due to their ease of synthesis and high selectivity. This article aims to review single and multiligand strategies critically. In addition, it highlights other strategies that integrate the effects of external stimuli, biomimetic approaches, and chemical approaches as nanocatalytic medicine, revealing their significant potential in treating GBM with peptide-functionalized NPs. Alternative routes of parenteral administration, specifically nose-to-brain delivery and local treatment within the resected tumor cavity, are also discussed. Finally, an overview of the significant obstacles and potential strategies to overcome them are discussed to provide a perspective on this promising field of GBM therapy.

Keywords: biomimetic approaches; blood−brain barrier (BBB); external stimuli; extracellular vesicles; glioblastoma; local treatment; nanocatalytic medicine; nanoparticles; nose-to-brain delivery; peptide functionalization.

Figure 1

Receptor profiling in glioblastoma. Schematic representation of critical receptors overexpressed in the BBB, GBM cells, and stem cells that have been exploited as targets for precision GBM therapy. Abbreviations: BBB: Blood-brain barrier; BTB: Blood tumor barrier; GBM: Glioblastoma. (Created with BioRender.com).

Figure 2

Innovative fusion: peptide surface modification meets external stimulation. Schematic representation of various external stimulation approaches—hyperthermia, photothermal therapy, magnetic delivery, ultrasound, and radiation therapy—that hold significant potential for enhancing the efficacy of GBM treatment regimens in combination with peptide functionalization. Abbreviations - BBB: Blood-brain barrier; NIR: Near-infrared spectroscopy. (Created with BioRender.com).

Figure 3

Cell membrane and endogenous protein camouflaged nanocarriers. This figure illustrates two prominent biomimetic approaches in decorated nanocarrier development for GBM treatment: membrane coating and self-assembly. Membrane coating involves RBC and GBM tumor cell membranes, imparting natural biological properties to nanocarriers for enhanced targeting and reduced immunogenicity. On the other hand, self-assembly uses serum albumin, lipoprotein, and ferritin to create nanocarriers with inherent structural advantages, optimizing therapeutic delivery to specific targets within the challenging GBM microenvironment. Abbreviations: GBM: Glioblastoma; NP: Nanoparticle; RBC: Red blood cell. (Created with BioRender.com)

Figure 4

(A) Illustration of GLIF mechanism in GL261 cells. H&E staining to brain slices of tumor-bearing mice. Adapted with permission from ref. Copyright 2023, Elsevier (B) Graphical representation for the ferroptosis therapy of brain tumors with cisplatin-loaded Fe₃O₄/Gd₂O₃ NPs decorated with Lf peptide and RGD2. In vivo results of treated mice bearing orthotopic brain tumors. Adapted with permission from ref. Copyright 2018, American Chemical Society (C) Schematic representation of ApoE-TBTP-Au NPs for ferroptosis therapy in orthotopic GBM-bearing mice model via thioredoxin reductase-HMOX1 axis. In vivo results of the tumor-bearing mice. Confocal images of labile iron (Fe²⁺), ROS, and lipid peroxidation in U87 cells stained with FerroOrange, DCFH-DA, and BODIPY probes, respectively. Adapted with permission under a Creative Commons CC BY license from ref. Copyright 2023, John Wiley and Sons (D) Schematic illustration of the enzymatic cascade initiated by ANG2-modified FeCDs nanozymes. In vivo efficacy in an orthotopic U87MG-Luc tumor-bearing nude mice. Adapted with permission from ref. Copyright 2022, Elsevier.

Figure 5

Delivery routes for targeted delivery in GBM treatment. (Created with BioRender.com).

Figure 6

Challenges in designing peptide-decorated nanocarriers: navigating the maze. This figure highlights key challenges in developing peptide-decorated nanocarriers for targeted drug delivery. It includes peptide instability, immunogenicity, targeting ligand surface density, receptor saturation phenomenon, limitations in the specificity of CPPs, and considerations for clinical translation. Addressing these hurdles is crucial to advancing the effectiveness and safety of nanocarrier-based therapies in clinical applications. Abbreviations: CPP: Cell-penetrating peptide. (Created with BioRender.com).

Figure 7

Strategies for overcoming peptide-decorated nanocarrier challenges. This figure illustrates different strategies to address challenges associated with peptide-decorated nanocarriers. Highlighted approaches include the integration of artificial intelligence and machine learning for optimized nanocarrier design, peptide stabilization through d-isomerization, stapled peptides, peptoid backbone modifications, terminal modifications, use of biotin-coupled peptides, and cyclization, modification of functional groups associated with PEG and the utilization of alternative polymers, the use of ionic liquids, control of ligand density and hindrance through dual-coating or covalent and noncovalent interactions and improvement of CPPs selectivity. Abbreviations: CPP: Cell-penetrating peptide; PAILs: Protein-avoidant ionic liquids; PEG: Polyethylene glycol. (Created with BioRender.com).