Peptide-Targeted Nanoparticles for Tumor Therapy: Vascular Homing Peptides Review-Special Topic on Phage Display Technology-Tekbiotech-Yeast and Phage Display CRO, Expert in Nano-body and Antibody Drug Development

Peptide-Targeted Nanoparticles for Tumor Therapy: Vascular Homing Peptides Review

Currently, chemotherapy remains the primary modality for cancer treatment. In an ideal scenario, systemically administered anticancer agents should accumulate specifically and efficiently at tumor sites, thereby minimizing off-target toxicity to healthy tissues. However, the majority of small-molecule chemotherapeutics lack cancer-specific targeting capabilities. Nanoparticles (NPs) can prolong drug circulation time by reducing renal clearance and protecting payloads from enzymatic degradation. Furthermore, NPs can be rationally engineered to achieve controlled and sustained drug release profiles. To enhance NP accumulation at diseased sites, affinity-based targeting strategies can be employed, wherein nanoparticles are conjugated with low-molecular-weight ligands such as peptides. These peptides can direct drug delivery and reduce off-target effects by binding to receptors expressed on the tumor vascular endothelium. A recent review, "Peptide-targeted nanoparticles for tumor therapy" (2025), systematically summarizes the latest advancements in the application of vascular homing peptides for tumor nanomedicine delivery.

图1靶向肽纳米颗粒概述.png

Figure 1: Overview of Peptide-Targeted Nanoparticles

1. Targets of Homing Peptides

In 1981, Auerbach demonstrated that endothelial cells express organ-specific antigens, postulating that these organ-specific molecules on endothelial cells might guide cancer cells toward organ-specific metastasis, and further proposed these molecules as potential therapeutic targets. The tumor vasculature exhibits significant morphological and biochemical differences from normal tissues, expressing a variety of angiogenesis-related molecules, including integrins and vascular endothelial growth factor receptors (VEGFRs). These molecules serve as targets for tumor-targeting peptides. Additionally, peptides can target proteins overexpressed on cancer cell surfaces that are typically localized intracellularly in healthy cells. Other research targets include immune cells within the tumor microenvironment, regulatory T cells, tumor-associated lymphatic vessels, and, importantly, the extracellular matrix. The application of phage display technology has accelerated the discovery of molecularly targeted peptides against these diverse targets.

2. Discovery of Homing Peptides – Phage Display Technology

George Smith et al. first described phage display technology in 1980, enabling screening against targets of varying complexity, including small molecules and living cells. In 1996, Erkki Ruoslahti's team achieved a major breakthrough in in vivo phage display technology. They injected peptide-phage libraries into live animals, subsequently recovering phages from the target tissues. These phages were then amplified and subjected to additional rounds of biopanning. Through this iterative selection process, phages capable of binding to target tissues or receptors were isolated. The peptides displayed on these phages, given their biological relevance, are more likely to prove effective in therapeutic or diagnostic applications.

图2体外 (A)和体内(B)噬菌体生物淘选技术示意图.png

Figure 2: Schematic of In Vitro (A) and In Vivo (B) Phage Biopanning

3. Advantages and Limitations of Homing Peptides

Over the past two decades, researchers have developed numerous tumor-targeting peptides to enhance the efficacy of anticancer nanoparticles. As affinity-targeting ligands, homing peptides offer several advantageous properties, including lack of species specificity, low immunogenicity, and high cost-effectiveness. Although homing peptides typically exhibit relatively low affinity (in the low micromolar or high nanomolar range), their conjugation onto nanoparticle surfaces enables multivalent delivery, thereby enhancing avidity and binding strength to target tissues, significantly improving both specificity and therapeutic outcomes.

图3血管归巢肽作为靶向配体的优势与局限性png.png

Figure 3: Advantages and Limitations of Vascular Homing Peptides as Targeting Ligands

Despite considerable progress in nanoparticle clinical research, less than 1% of administered NPs accumulate at tumor sites. This is primarily attributed to physiological barriers within the tumor microenvironment, immune clearance, protein corona formation, the availability and density of target receptors, and the intrinsic pharmacokinetic limitations of NPs. Nevertheless, despite this overall low delivery efficiency, targeting peptides significantly improve the biodistribution and therapeutic efficacy of NPs—for example, by increasing local NP concentrations within tumors, promoting deeper tumor penetration, and reducing toxicity to normal tissues.

Reference:

[1] Sidorenko V, Tobi A, Sugahara KN, Teesalu T. Peptide-targeted nanoparticles for tumor therapy. J Control Release. 2025 Nov 10;387:114195.

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