Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells

Academic Background

With the intensification of population aging, the accumulation of senescent cells is considered a significant hallmark of aging and age-related diseases. Senescent cells are not only associated with tissue functional decline but are also regarded as a side effect of anticancer therapies, potentially leading to drug resistance and treatment failure. Therefore, drugs that selectively induce death in senescent cells (senolytics) have become a hotspot in anti-aging and anticancer research. However, the first-generation senolytics have limitations, such as off-target effects and systemic toxicity. To address these issues, researchers have begun designing more targeted senolytics, particularly those based on nanotechnology (nanosenolytics). This study aims to develop a multifunctional nanoplatform based on magnetic nanoparticles (MNPs) that targets the senescent cell surface marker CD26 and incorporates the HSP90 inhibitor 17-DMAG to achieve selective clearance of senescent cells.

Source of the Paper

This paper was co-authored by Maciej Wnuk, Susel Del Sol-Fernández, and others, with the research team coming from multiple institutions, including research units in Poland and Spain. The paper was published in 2025 in the journal ACS Biomaterials Science & Engineering, titled “Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells.”

Research Process and Results

1. Research Design

This study designed a multifunctional nanoplatform composed of iron oxide nanoparticles (MNPs) functionalized with an anti-CD26 antibody and loaded with the HSP90 inhibitor 17-DMAG (MNP@CD26@17D). The platform aims to target and eliminate oxidative stress-induced senescent human fibroblasts (WI-38 and BJ cells) and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells.

2. Synthesis and Functionalization of the Nanoplatform

• Synthesis of MNPs: Iron oxide nanoparticles coated with oleic acid (OA) (MNP@OA) were synthesized via thermal decomposition, with an average size of 13.2±1.3 nm.
• Aqueous Phase Transfer: Hydrophobic MNPs were transferred to the aqueous phase using the amphiphilic polymer PMAO, forming MNP@PMAO.
• Functionalization and Drug Loading: Streptavidin (STV) was conjugated to the MNPs surface via EDC/NHS chemistry, and the remaining active groups were passivated with PEG 750 Da. Subsequently, a biotin-modified CD26 antibody was attached to the MNPs, forming MNP@CD26. Finally, the HSP90 inhibitor 17-DMAG was loaded onto the MNPs, resulting in MNP@CD26@17D.

3. Characterization of the Nanoplatform

• Physicochemical Properties: The size, shape, surface chemistry, and organic content of the MNPs were characterized using transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA).
• Drug Loading Efficiency: The loading efficiency of 17-DMAG was approximately 30%, as determined by UV-Vis spectroscopy.

4. Biological Effects of the Nanoplatform

• Targeting and Elimination of Senescent Cells: The study found that CD26 expression was significantly increased in oxidative stress-induced senescent fibroblasts and anticancer drug-induced senescent skin cancer cells. MNP@CD26@17D effectively targeted and eliminated these senescent cells.
• Mechanisms of Cell Death: MNP@CD26@17D induced a dual response in senescent cells: an early (2-hour) response dominated by apoptosis and a late (24-hour) response dominated by ferroptosis. Ferroptosis may be executed through ferritinophagy, as evidenced by elevated levels of the ferritinophagy marker NCOA4 and a reduced ferritin pool.

5. Biocompatibility Testing

• Hemolysis Assay: MNP@CD26@17D did not cause hemolysis in human erythrocytes within 24 hours, indicating good biocompatibility.

Conclusions and Significance

This study successfully developed a magnetic nanoplatform based on CD26 targeting and HSP90 inhibition, which effectively clears senescent cells. The platform operates through dual mechanisms of apoptosis and ferroptosis, providing a new strategy for anti-aging and anticancer therapies. Additionally, the nanoplatform exhibits good biocompatibility, laying the foundation for its clinical application.

Research Highlights

1. High Targeting Specificity: The anti-CD26 antibody precisely targets senescent cells, reducing side effects on normal cells.
2. Dual Mechanisms: The platform clears senescent cells through both apoptosis and ferroptosis, enhancing therapeutic efficacy.
3. Excellent Biocompatibility: The nanoplatform demonstrated good biocompatibility in vitro, making it a promising candidate for clinical use.

Additional Valuable Information

This study also revealed increased CD26 expression in anticancer drug-induced senescent cancer cells, providing new evidence for the broad application of CD26 as a senescence marker. Furthermore, the discovery of the ferroptosis mechanism offers a new research direction for the clearance of senescent cells.